Substituted oxazolidinones and their in the field of blood coagulation

ABSTRACT

The invention relates to the field of blood coagulation. Novel oxazolidinone derivatives of the general formula (I)  
                 
 
     processes for their preparation and their use as medicinally active compounds for the prophylaxis and/or treatment of disorders are described.

[0001] The present invention relates to the field of blood coagulation.In particular, the present invention relates to novel oxazolidinonederivatives, to processes for their preparation and to their use asactive compounds in medicaments.

[0002] Blood coagulation is a protective mechanism of the organism whichhelps to “seal” defects in the wall of the blood vessels quickly andreliably. Thus, loss of blood can be avoided or kept to a minimum.Haemostasis after injury of the blood vessels is effected mainly by thecoagulation system in which an enzymatic cascade of complex reactions ofplasma proteins is triggered. Numerous blood coagulation factors areinvolved in this process, each of which factors converts, on activation,the respectively next inactive precursor into its active form. At theend of the cascade comes the conversion of soluble fibrinogen intoinsoluble fibrin, resulting in the formation of a blood clot. In bloodcoagulation, traditionally the intrinsic find the extrinsic system,which end in a joint reaction path, are distinguished. Here factor Xa,which is formed from the proenzyme factor X, plays a key role, since itconnects the two coagulation paths. The activated serine protease Xacleaves prothrombin to thrombin. The resulting thrombin, in turn,cleaves fibrinogen to fibrin, a fibrous/gelatinous coagulant. Inaddition, thrombin is a potent effector of platelet aggregation whichlikewise contributes significantly to haemostasis.

[0003] Maintenance of normal haemostasis—between bleeding andthrombosis—is subject to a complex regulatory mechanism. Uncontrolledactivation of the coagulant system or defective inhibition of theactivation processes may cause formation of local thrombi or embolismsin vessels (arteries, veins, lymph vessels) or in heart cavities. Thismay lead to serious disorders, such as myocardial infarct, anginapectoris (including unstable angina), reocclusions and restenoses afterangioplasty or aortocoronary bypass, stroke, transitory ischaemicattacks, peripheral arterial occlusive disorders, pulmonary embolisms ordeep venous thromboses; hereinbelow, these disorders are collectivelyalso referred to as thromboembolic disorders. In addition, in the caseof consumption coagulopathy, hypercoagulability may—systemically—resultin disseminated intravascular coagulation.

[0004] These thromboembolic disorders are the most frequent cause ofmorbidity and mortality in most industrialized countries (Pschyrembel,Klinisches Wörterbuch [clinical dictionary], 257^(th) edition, 1994,Walter de Gruyter Verlag, page 199 ff., entry “Blutgerinnung” [bloodcoagulation]; Römpp Lexikon Chemie, Version 1.5, 1998, Georg ThiemeVerlag Stuttgart, entry “Blutgerinnung”; Lubert Stryer, Biochemie[biochemistry], Spektrum der Wissenschaft Verlagsgesellschaft mbHHeidelberg, 1990, page 259 ff.).

[0005] The anticoagulants, i.e. substances for inhibiting or preventingblood coagulation, which are known from the prior art have various,often grave disadvantages. Accordingly, in practice, an efficienttreatment method or prophylaxis of thromboembolic disorders is verydifficult and unsatisfactory.

[0006] In the therapy and prophylaxis of thromboembolic disorders, useis firstly made of heparin, which is administered parenterally orsubcutaneously. Owing to more favourable pharmacokinetic properties,preference is nowadays more and more given to low-molecular-weightheparin; however, even with low-molecular-weight heparin, it is notpossible to avoid the known disadvantages described below, which areinvolved in heparin therapy. Thus, heparin is ineffective whenadministered orally and has a relatively short half-life. Since heparininhibits a plurality of factors of the blood coagulation cascade at thesame time, the action is nonselective. Moreover, there is a high risk ofbleeding; in particular, brain haemorrhages and gastrointestinalbleeding may occur, which may result in thrombopenia, drug-inducedalopecia or osteoporosis (Pschyrembel, Klinisches Wörterbuch, 257^(th)edition, 1994, Walter de Gruyter Verlag, page 610, entry “Heparin”;Römpp Lexikon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart,entry “Heparin”).

[0007] A second class of anticoagulants are the vitamin K antagonists.These include, for example, 1,3-indanediones, and especially compoundssuch as warfarin, phenprocoumon, dicumarol and other coumarinderivatives which inhibit the synthesis of various products of certainvitamin K-dependent coagulation factors in the liver in a non-selectivemanner. Owing to the mechanism of action, however, the onset of theaction is very slow (latency to the onset of action 36 to 48 hours). Itis possible to administer the compounds orally; however, owing to thehigh risk of bleeding and the narrow therapeutic index, a time-consumingindividual adjustment and monitoring of the patient are required.Moreover, other adverse effects, such as gastrointestinal disturbances,hair loss and skin necroses, have been described (Pschyrembel,Klinisches Wörterbuch, 257^(th) edition, 1994, Walter de Gruyter Verlag,page 292 ff., entry “coumarin derivatives”; Ullmann's Encyclopedia ofIndustrial Chemistry, 5^(th) edition, VCH Verlagsgesellschaft, Weinheim,1985-1996, entry “vitamin K”).

[0008] Recently, a novel therapeutic approach for the treatment andprophylaxis of thromboembolic disorders has been described. This noveltherapeutic approach aims to inhibit factor Xa (cf. WO-A-99/37304;WO-A-99/06371; J. Hauptmann, J. Stürzebecher, Thrombosis Research 1999,93, 203; F. Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors by classicaland combinatorial chemistry, DDT 1998, 3, 223; F. Al-Obeidi, J. A.Ostrem, Factor Xa inhibitors, Exp. Opin. Ther. Patents 1999, 9, 931; B.Kaiser, Thrombin and factor Xa inhibitors, Drugs of the Future 1998, 23,423; A. Uzan, Antithrombotic agents, Emerging Drugs 1998, 3, 189; B. -Y.Zhu, R. M. Scarborough, Curr. Opin. Card. Pulm. Ren. Inv. Drugs 1999, 1(1), 63). It has been shown that, in animal models, various bothpeptidic and nonpeptidic compounds are effective as factor Xainhibitors.

[0009] Accordingly, it is an object of the present invention to providenovel substances for controlling disorders, which substances have a widetherapeutic spectrum.

[0010] In particular, they should be suitable for a more efficientprophylaxis and/or treatment of thromboembolic disorders, avoiding—atleast to some extent—the disadvantages of the prior art described above,where the term “thromboembolic disorders” in the context of the presentinvention is to be understood as meaning, in particular, seriousdisorders, such as myocardial infarct, angina pectoris (includingunstable angina), reocclusions and restenoses after angioplasty oraortocoronary bypass, stroke, transitory ischaemic attacks, peripheralarterial occlusive disorders, pulmonary embolisms or deep venousthromboses.

[0011] It is another object of the present invention to provide novelanticoagulants which inhibit the blood coagulation factor Xa withincreased selectivity, avoiding—at least to some extent—the problems ofthe therapeutic methods for thromboembolic disorders known from theprior art.

[0012] Accordingly, the present invention provides substitutedoxazolidinones of the general formula (I)

[0013] in which:

[0014] R¹ represents optionally benzo-fused thiophene (thienyl) whichmay optionally be mono- or polysubstituted;

[0015] R² represents any organic radical;

[0016] R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and eachrepresents hydrogen or represents (C₁-C₆)-alkyl

[0017] and their pharmaceutically acceptable salts, hydrates andprodrugs,

[0018] except for compounds of the general formula (I) in which theradical R¹ is an unsubstituted 2-thiophene radical and the radical R² issimultaneously a mono- or polysubstituted phenyl radical and theradicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

[0019] Preference is given here to compounds of the general formula (I),

[0020] in which

[0021] R¹ represents optionally benzo-fused thiophene (thienyl) whichmay optionally be mono- or polysubstituted by a radical from the groupconsisting of halogen; cyano; nitro; amino; aminomethyl; (C₁-C₈)-alkylwhich for its part may optionally be mono- or polysubstituted byhalogen; (C₃-C₇)-cycloalkyl; (C₁-C₈)-alkoxy; imidazolinyl; —C(═NH)NH₂;carbamoyl; and mono- and di-(C₁-C₄)-alkyl-aminocarbonyl,

[0022] R² represents one of the groups below:

[0023] A-,

[0024] A-M-,

[0025] D-M-A-,

[0026] B-M-A-,

[0027] B-,

[0028] B-M-,

[0029] B-M-B-,

[0030] D-M-B-,

[0031] where:

[0032] the radical “A” represents (C₆-C₁₄)-aryl, preferably(C₆-C₁₀)-aryl, in particular phenyl or naphthyl, very particularlypreferably phenyl;

[0033] the radical “B” represents a 5- or 6-membered aromaticheterocycle which contains up to 3 heteroatoms and/or hetero chainmembers, in particular up to 2 heteroatoms and/or hetero chain members,from the group consisting of S, N, NO (N-oxide) and O;

[0034] the radical “D” represents a saturated or partially unsaturated,mono- or bicyclic, optionally benzo-fused 4- to 9-membered heterocyclewhich contains up to three heteroatoms and/or hetero chain members fromthe group consisting of S, SO, SO₂, N, NO (N-oxide) and O;

[0035] the radical “M” represents —NH—, —CH₂—, —CH₂CH₂—, —O—, —NH—CH₂—,—CH₂—NH—, —OCH₂—, —CH₂O—, —CONH—, —NHCO—, —COO—, —OOC—, —S—, —SO₂— orrepresents a covalent bond;

[0036] where

[0037] the groups “A”, “B” and “D” defined above may each optionally bemono- or polysubstituted by a radical from the group consisting ofhalogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl;(C₁-C₆)-alkanoyl; (C₃-C₇)-cycloalkanoyl; (C₆-C₁₄)-arylcarbonyl;(C₅-C₁₀)-heteroarylcarbonyl; (C₁-C₆)-alkanoyloxymethyloxy;(C₁-C₄)-hydroxy-alkylcarbonyl; —COOR²⁷; —SO₂R²⁷; C(NR²⁷R²⁸)═NR²⁹;—CONR²⁸R²⁹; —SO₂NR²⁸R²⁹; —OR³⁰; —NR³⁰OR³¹, (C₁-C₆)-alkyl and(C₃-C₇)-cycloalkyl, where (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl for theirpart may optionally be substituted by a radical from the groupconsisting of cyano; —OR²⁷; —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸) and—C(NR²⁷R²⁸)═NR²⁹,

[0038] where:

[0039] v is either 0 or 1 and

[0040] R²⁷, R²⁸ and R²⁹ are identical or different and independently ofone another each represents hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₁-C₄)-alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl, and/or

[0041] R²⁷ and R²⁸ or R²⁷ and R²⁹ toether with the nitrogen atom towhich they are attached form a saturated or partially unsaturated 5- to7-membered heterocycle having up to three, preferably up to two,identical or different heteroatoms from the group consisting of N, O andS, and

[0042] R³⁰ and R³¹ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₁-C₄)-alkylsulphonyl, (C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl,di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, —CH₂C(NR²⁷R²⁸)═NR²⁹ or —COR³³,

[0043] where

[0044] R³³ represents (C₁-C₆)-alkoxy, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,(C₁-C₄)-alkoxycarbonyl-(C₁-C₄)-alkyl, (C₁-C₄)-aminoalkyl,(C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkanoyl-(C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, (C₁-C₆)-alkenyl, (C₁-C₈)-alkyl, which may optionallybe substituted by phenyl or acetyl, (C₆-C₁₄)-aryl, (C₅-C₁₀)-heteroaryl,trifluoromethyl, tetrahydrofuranyl or butyrolactone,

[0045] R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and eachrepresents hydrogen or represents (C₁-C₆)-alkyl

[0046] and their pharmaceutically acceptable salts, hydrates andprodrugs,

[0047] except for compounds of the general formula (I) in which theradical R¹ is an unsubstituted 2-thiophene radical and the radical R² issimultaneously a mono- or polysubstituted phenyl radical and theradicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

[0048] Preference is also given here to compounds of the general formula(I),

[0049] in which

[0050] R¹ represents thiophene (thienyl), in particular 2-thiophene,which may optionally be mono- or polysubstituted by halogen, preferablychlorine or bromine, by amino, aminomethyl or (C₁-C₈)-alkyl, preferablymethyl, where the (C₁-C₈)-alkyl radical for its part may optionally bemono- or polysubstituted by halogen, preferably fluorine,

[0051] R² represents one of the groups below:

[0052] A-,

[0053] A-M-,

[0054] D-M-A-,

[0055] B-M-A-,

[0056] B-,

[0057] B-M-,

[0058] B-M-B-,

[0059] D-M-B-,

[0060] where:

[0061] the radical “A” represents (C₆-C₁₄)-aryl, preferably(C₆-C₁₀)-aryl, in particular phenyl or naphthyl, very particularlypreferably phenyl;

[0062] the radical “B” represents a 5- or 6-membered aromaticheterocycle which contains up to 3 heteroatoms and/or hetero chainmembers, in particular up to 2 heteroatoms and/or hetero chain members,from the group consisting of S, N, NO (N-oxide) and O;

[0063] the radical “D” represents a saturated or partially unsaturated 4to 7-membered heterocycle which contains up to three heteroatoms and/orhetero chain members from the group consisting of S, SO, SO₂, N, NO(N-oxide) and O;

[0064] the radical “M” represents —NH—, —CH₂—, —CH₂CH₂—, —O—, —NH—CH₂—,—CH₂—NH—, —OCH₂—, —CH₂O—, —CONH—, —NHCO—, —COO—, —OOC—, —S— orrepresents a covalent bond;

[0065] where

[0066] the groups “A”, “B” and “D” defined above may in each caseoptionally be mono- or polysubstituted by a radical from the groupconsisting of halogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl;pyridyl; (C₁-C₆)-alkanoyl; (C₃-C₇)-cycloalkanoyl; (C₆-C₁₄)-arylcarbonyl;(C₅-C₁₀)-heteroarylcarbonyl; (C₁-C₆)-alkanoyloxymethyloxy; —COOR²⁷;—SO₂R²⁷; —C(NR²⁷R²⁸)═NR²⁹; —CONR R²⁸R²⁹; —SO₂NR²⁸R²⁹; —OR³⁰; —NR³⁰R³¹,(C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl,

[0067] where (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl for their part mayoptionally be substituted by a radical from the group consisting ofcyano; —OR²⁷; —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸) and —C(NR²⁷R²⁸ )═NR²⁹,

[0068] where:

[0069] v is either 0 or 1 and

[0070] R²⁷, R²⁸ and R²⁹ are identical or different and independently ofone another each represents hydrogen, (C₁-C₄)-alkyl or(C₃-C₇)-cycloalkyl, and/or

[0071] R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom towhich they are attached form a saturated or partially unsaturated 5- to7-membered heterocycle having up to three, preferably up to two,identical or different heteroatoms from the group consisting of N, O andS, and

[0072] R³⁰ and R³¹ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₁-C₄)-alkylsulphonyl, (C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl,di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, (C₁-C₄)-alkanoyl,(C₆-C₁₄)-arylcarbonyl, (C₅-C₁₀)-heteroarylcarbonyl,(C₁-C₄)-alkylaminocarbonyl or —CH₂C(NR²⁷R²⁸)═NR²⁹,

[0073] R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and eachrepresents hydrogen or represents (C₁-C₆)-alkyl

[0074] and their pharmaceutically acceptable salts, hydrates andprodrugs,

[0075] except for compounds of the general formula (I) in which theradical R¹ is an unsubstituted 2-thiophene radical and the radical R² issimultaneously a mono- or polysubstituted phenyl radical and theradicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

[0076] Particular preference is given here to compounds of the generalformula (I),

[0077] in which

[0078] R¹ represents thiophene (thienyl), in particular 2-thiophene,which may optionally be mono- or polysubstituted by halogen, preferablychlorine or bromine, or by (C₁-C₈)-alkyl, preferably methyl, where the(C₁-C₈)-alkyl radical for its part may optionally be mono- orpolysubstituted by halogen, preferably fluorine,

[0079] R² represents one of the groups below:

[0080] A-,

[0081] A-M-,

[0082] D-M-A-,

[0083] B-M-A-,

[0084] B-,

[0085] B-M-,

[0086] B-M-B-,

[0087] D-M-B-,

[0088] where:

[0089] the radical “A” represents phenyl or naphthyl, in particularphenyl;

[0090] the radical “B” represents a 5- or 6-membered aromaticheterocycle which contains up to 2 heteroatoms from the group consistingof S, N, NO (N-oxide) and O;

[0091] the radical “D” represents a saturated or partially unsaturated5- or 6-membered heterocycle which contains up to two heteroatoms and/orhetero chain members from the group consisting of S, SO, SO₂, N, NO(N-oxide) and O;

[0092] the radical “M” represents —NH—, —O—, —NH—CH₂—, —CH₂—NH—, —OCH₂—,—CH₂O—, —CONH—, —NHCO— or represents a covalent bond;

[0093] where

[0094] the groups “A”, “B” and “D” defined above may in each caseoptionally be mono- or polysubstituted by a radical from the groupconsisting of halogen; trifluoromethyl; oxo; cyano; pyridyl;(C₁-C₃)-alkanoyl; (C₆-C₁₀)-arylcarbonyl; (C₅-C₆)-heteroarylcarbonyl;(C₁-C₃)-alkanoyloxymethyloxy; —C(NR²⁷R²⁸)═NR²⁹; —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹;—OH; —NR³⁰R³¹; (C₁-C₄)-alkyl; and cyclopropyl, cyclopentyl orcyclohexyl,

[0095] where (C₁-C₄)-alkyl and cyclopropyl, cyclopentyl or cyclohexylfor their part may optionally be substituted by a radical from the groupconsisting of cyano; —OH; —OCH₃; —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸) and—C(NR²⁷R²⁸)═NR²⁹,

[0096] where:

[0097] v is either 0 or 1, preferably 0, and

[0098] R²⁷, R²⁸ and R²⁹ are identical or different and independently ofone another each represents hydrogen, (C₁-C₄)-alkyl or else cyclopropyl,cyclopentyl or cyclohexyl

[0099] and/or

[0100] R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom towhich they are attached may form a saturated or partially unsaturated 5-to 7-membered heterocycle having up to two identical or differentheteroatoms from the group consisting of N, O and S, and

[0101] R³⁰ and R³¹ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl, cyclopropyl,cyclopentyl, cyclohexyl, (C₁-C₄)-alkylsulphonyl, (C₁-C₄)-hydroxyalkyl,(C₁-C₄)-aminoalkyl, di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl,(C₁-C₃)-alkanoyl or phenylcarbonyl,

[0102] R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and eachrepresents hydrogen or represents (C₁-C₆)-alkyl

[0103] and their pharmaceutically acceptable salts, hydrates andprodrugs,

[0104] except for compounds of the general formula (I) in which theradical R¹ is an unsubstituted 2-thiophene radical and the radical R² issimultaneously a mono- or polysubstituted phenyl radical and theradicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

[0105] Particular preference is given here to compounds of the generalformula (I),

[0106] in which

[0107] R¹ represents 2-thiophene which may optionally be substituted inthe 5-position by a radical from the group consisting of chlorine,bromine, methyl or trifluoromethyl,

[0108] R² represents one of the groups below:

[0109] A-,

[0110] A-M-,

[0111] D-M-A-,

[0112] B-M-A-,

[0113] B-,

[0114] B-M-,

[0115] B-M-B-,

[0116] D-M-B-,

[0117] where:

[0118] the radical “A” represents phenyl or naphthyl, in particularphenyl;

[0119] the radical “B” represents a 5- or 6-membered aromaticheterocycle which contains up to 2 heteroatoms from the group consistingof S, N, NO (N-oxide) and O;

[0120] the radical “D” represents a saturated or partially unsaturated5- or 6-membered heterocycle which contains a nitrogen atom andoptionally a further heteroatom and/or hetero chain member from thegroup consisting of S, SO, SO₂ and O; or contains up to two heteroatomsand/or hetero chain members from the group consisting of S, SO, SO₂ andO;

[0121] the radical “M” represents —NH—, —O—, —NH—CH₂—, —CH₂—NH—, —OCH₂—,—CH₂O—, —CONH—, —NHCO— or represents a covalent bond;

[0122] where

[0123] the groups “A”, “B” and “D” defined above may in each caseoptionally be mono- or polysubstituted by a radical from the groupconsisting of halogen; trifluoromethyl; oxo; cyano; pyridyl;(C₁-C₃)-alkanoyl; (C₆-C₁₀)-arylcarbonyl; (C₅-C₆)-heteroarylcarbonyl;(C₁-C₃)-alkanoyloxyrnethyloxy; —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹; —OH; —NR³⁰R³¹;(C₁-C₄)-alkyl; and cyclopropyl, cyclopentyl or cyclohexyl, where(C₁-C₄)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their partmay optionally be substituted by a radical from the group consisting ofcyano; —OH; —OCH₃; —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸) and —C(NR²⁷R²⁸)═NR²⁹,

[0124] where:

[0125] v is either 0 or 1, preferably 0, and

[0126] R²⁷, R²⁸ and R²⁹ are identical or different and independently ofone another each represents hydrogen, (C₁-C₄)-alkyl or else cyclopropyl,cyclopentyl or cyclohexyl

[0127] and/or

[0128] R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom towhich they are attached may form a saturated or partially unsaturated 5-to 7-membered heterocycle having up to two identical or differentheteroatoms from the group consisting of N, O and S, and

[0129] R³⁰ and R³¹ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl, cyclopropyl,cyclopentyl, cyclohexyl, (C₁-C₄)-alkylsulphonyl, (C₁-C₄)-hydroxyalkyl,(C₁-C₄)-aminoalkyl, di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl,(C₁-C₃)-alkanoyl or phenylcarbonyl,

[0130] R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and eachrepresents hydrogen or represents (C₁-C₄)-alkyl

[0131] and their pharmaceutically acceptable salts, hydrates andprodrugs,

[0132] except for compounds of the general formula (I) in which theradical R¹ is an unsubstituted 2-thiophene radical and the radical R² issimultaneously a mono- or polysubstituted phenyl radical and theradicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

[0133] Very particular preference is given here to compounds of thegeneral formula (I),

[0134] in which

[0135] R¹ represents 2-thiophene which is substituted in the 5-positionby a radical from the group consisting of chlorine, bromine, methyl andtrifluoromethyl,

[0136] R² represents D-A-:

[0137] where:

[0138] the radical “A” represents phenylene;

[0139] the radical “D” represents a saturated 5- or 6-memberedheterocycle, which is attached to “A” via a nitrogen atom, which has acarbonyl group directly adjacent to the linking nitrogen atom and

[0140] in which one carbon ring member may be replaced by a heteroatomfrom the group consisting of S, N and O;

[0141] where

[0142] the group “A” defined above may optionally be mono- ordisubstituted in the meta position with respect to the point ofattachment to the oxazolidinone, by a radical from the group consistingof fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano,

[0143] R³, R⁴, R⁵, R⁶, R⁷ and R⁸ each represent hydrogen

[0144] and their pharmaceutically acceptable salts, hydrates andprodrugs.

[0145] Very particular preference is also given here to the compoundhaving the following formula

[0146] and to its pharmaceutically acceptable salts, hydrates andprodrugs.

[0147] In the compounds of the general formula (I) above, the radical

[0148] R¹ may in particular represent optionally benzo-fused thiophene(thienyl) which may optionally be mono- or polysubstituted by a radicalfrom the group consisting of halogen; cyano; nitro; (C₁-C₈)-alkyl, whichfor its part may optionally be mono- or polysubstituted by halogen;(C₃-C₇)-cycloalkyl; (C₁-C₈)-alkoxy; imidazolinyl; —C(═NH)NH₂; carbamoyl;and mono- and di-(C₁-C₄)-alkylaminocarbonyl.

[0149] In the compounds of the general formula (I), the radical

[0150] R¹ may preferably represent thiophene (thienyl), in particular2-thiophene, which may optionally be mono- or polysubstituted byhalogen, preferably chlorine or bromine, or by (C₁-C₈)-alkyl, preferablymethyl, where the (C₁-C₈)-alkyl radical, preferably the methyl radical,may for its part optionally be mono- or polysubstituted by halogen,preferably fluorine.

[0151] In the compounds of the general formula (I), the radicals

[0152] R³, R⁴, R⁵, R⁶, R⁷ and R⁸ may be identical or different and mayrepresent, in particualr, hydrogen or (C₁-C₆)-alkyl, preferably hydrogenor (C₁-C₄)-alkyl, very particularly preferably hydrogen.

[0153] The radical R², i.e. the organic radical, can in particular beselected from the substituent groups listed below:

[0154] In the compounds of the general formula (I), the radical

[0155] R² may, in particular, represent a group of the followingformula:

Y—X′—(CH₂)_(p)—X—(CO)_(n)—(CH₂)_(o) ₁ —(CR⁹R¹⁰)_(m)—(CH₂)_(o) ₂ —

[0156] where:

[0157] m is an integer from 0 to 6, preferably from 1 to 3,

[0158] n is either 0 or 1,

[0159] p is an integer from 0 to 3, preferably either 0 or 1,

[0160] o₁ is an integer 0 or 1,

[0161] o₂ is an integer 0 or 1,

[0162] R⁹ and R₁₀ are identical or different and each representshydrogen; (C₁-C₄)-alkyl, preferably methyl; (C₁-C₄)-alkoxy, preferablymethoxy; (C₃-C₇)-cycloalkyl; hydroxyl or fluorine,

[0163] X and X′ are identical or different and each represents O; N—R¹¹or a covalent bond,

[0164] where R¹¹ represents H; (C₁-C₄)-alkyl, preferably methyl, or(C₃-C₇)-cycloalkyl,

[0165] Y represents a 3- to 7-membered saturated or partiallyunsaturated cyclic hydrocarbon radical which optionally contains 1 to 3identical or different heteroatoms and/or hetero chain members from thegroup consisting of N, O, S, SO and SO₂,

[0166] where:

[0167] this radical Y may optionally be substituted by a 5- or6-membered aromatic or a 3- to 7-membered saturated or partiallyunsaturated cyclic hydrocarbon radical which optionally contains up to 3identical or different heteroatoms from the group consisting of N, O andS and

[0168] where this radical may for its part optionally be substituted bya radical from the group consisting of cyano; hydroxyl; halogen;(C₁-C₄)-alkyl; —C(═NR¹²)NR¹³R¹³; and —NR¹⁴R¹⁵,

[0169] where:

[0170] R¹² represents hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl;

[0171] R¹³ and R^(13′) are identical or different and independently ofone another each represents hydrogen, (C₁-C₄)-alkyl or(C₃-C₇)-cycloalkyl and/or

[0172] R¹³ and R^(13′) together with the N atom to which they areattached form a 5- to 7-membered heterocycle which may optionallycontain up to 2 further heteroatoms from the group consisting of N, Oand S;

[0173] R¹⁴ and R¹⁵ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl or(C₁-C₅)-alkanoyl;

[0174] and/or

[0175] this radical Y may furthermore optionally be substituted by aradical from the group consisting of oxo; cyano; thiono; halogen; —OR¹⁶;═NR¹⁶; —NR¹⁶R¹⁷; —C(═NR¹⁸)NR¹⁹R^(19′) and (C₁-C₄)-alkyl,

[0176] in which (C₁-C₄)-alkyl for its part may optionally be substitutedby a radical from the group consisting of hydroxyl; cyano; —NR¹⁶R¹⁷ and—C(═NR¹⁸)NR¹⁹R^(19′),

[0177] where:

[0178] R¹⁶ and R¹⁷ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl or(C₁-C₃)-alkanoyl;

[0179] R¹⁸ represents hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl;

[0180] R¹⁹ and R^(19′) are identical or different and independently ofone another each represents hydrogen, (C₁-C₄)-alkyl or(C₃-C₇)-cycloalkyl and/or

[0181] R¹⁹ and R^(19′) together with the N atom to which they areattached form a 5- to 7-membered heterocycle which may optionallycontain up to 2 further heteroatoms from the group consisting of N, Oand S.

[0182] Particular preference is given to compounds of the generalformula (I) in which the radical

[0183] R² represents a group of the following formula:

Y—X′—(CH₂)_(p)—X—(CO)_(n)—(CH₂)_(o) ₁ —(CR⁹R¹⁰)_(m)—(CH₂)_(o) ₂ —

[0184] where

[0185] m is an integer from 0 to 3,

[0186] n is an integer 0 or 1,

[0187] p is an integer 0 or 1,

[0188] o₁ is an integer 0 or 1,

[0189] o₂ is an integer 0 or 1,

[0190] R⁹ and R¹⁰ are identical or different and each representshydrogen; methyl; methoxy; hydroxyl or fluorine,

[0191] X and X′ are identical or different and each represents O; N—R¹¹or a covalent bond,

[0192] where R¹¹ represents H or methyl,

[0193] Y represents a 5- to 7-membered saturated cyclic hydrocarbonradical which optionally contains 1 or 2 identical or differentheteroatoms and/or hetero chain members from the group consisting of N,O, S, SO and SO₂, in particular cyclohexyl, piperazinyl, morpholinyl,thiomorpholinyl, diazepinyl, pyrrolidinyl and piperidinyl,

[0194] where:

[0195] this radical Y may optionally be substituted by a 5- or6-membered aromatic or a 5- to 7-membered saturated or partiallyunsaturated cyclic hydrocarbon radical which optionally contains up to 2identical or different heteroatoms from the group consisting of N, O andS and

[0196] where this radical for its part may be substituted by a radicalfrom the group consisting of cyano; hydroxyl; fluorine; chlorine;(C₁-C₄)-alkyl; —C(═NR¹²)NR¹³R^(13′); and —NR¹⁴R¹⁵,

[0197] where:

[0198] R¹² represents hydrogen, methyl, ethyl, cyclopropyl, cyclopentylor cyclohexyl;

[0199] R¹³ and R^(13′) are identical or different and independently ofone another each represents hydrogen, methyl, ethyl, cyclopropyl,cyclopentyl or cyclohexyl and/or

[0200] R¹³ and R^(13′) together with the N atom to which they areattached form a 5- to 7-membered heterocycle which may optionallycontain up to 2 further heteroatoms from the group consisting of N, Oand S, in particular piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl;

[0201] R¹⁴ and R¹⁵ are identical or different and independently of oneanother each represents hydrogen, methyl, ethyl, cyclopropyl,cyclopentyl or cyclohexyl or else acetyl;

[0202] and/or

[0203] this radical Y may furthermore optionally be substituted by aradical from the group consisting of oxo; cyano; thiono; fluorine;chlorine; —OH; —OCH₃; ═NR¹⁶; —NH₂; —N(CH₃)₂; —C(═NR¹⁸)NR¹⁹R^(19′) andmethyl,

[0204] in which methyl for its part may optionally be substituted by aradical from the group consisting of hydroxyl; cyano; —NR¹⁶R¹⁷ and—C(═NR¹⁸)NR¹⁹R^(19′),

[0205] where:

[0206] R¹⁶ and R¹⁷ are identical or different and independently of oneanother each represents hydrogen, methyl, (C₃-C₇)-cycloalkyl or acetyl;

[0207] R¹⁸ reprsents hydrogen, methyl or (C₃-C₇)-cycloalkyl;

[0208] R⁹ and R^(19′) are identical or different and independently ofone another each represents hydrogen, methyl or (C₃-C₇)-cycloalkyland/or

[0209] R¹⁹ and R^(19′) together with the N atom to which they areattached form a 5- to 7-membered heterocycle which may optionallycontain up to 2 further heteroatoms from the group consisting of N, Oand S, in particular piperidinyl, piperazinyl, morpholinyl andthio-morpholinyl.

[0210] Likewise, in the compounds of the general formula (I), theradical

[0211] R² may represent a group of the formula below:

Z—(CO)_(t)—(CR²⁰R²¹)_(s)—

[0212] where:

[0213] s is an integer from 1 to 6,

[0214] t is either 0 or 1,

[0215] R²⁰ and R²¹ are identical or different and each representshydrogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, (C₃-C₇)-cycloalkyl, hydroxyl orfluorine,

[0216] Z represents a radical which is selected from the groupconsisting of cyano; —C(NR²²R²³)═NR²⁴; —CO(NH)_(u)NR²²R²³; and —NR²⁵R²⁶,

[0217] where:

[0218] u is either 0 or 1, preferably 0, and

[0219] R²², R²³ and R²⁴ are identical or different and independently ofone another each represents hydrogen, (C₁-C₄)-alkyl or(C₃-C₇)-cycloalkyl, preferably hydrogen or methyl, and/or

[0220] R²² and R²³ together with the N atom to which they are attachedform a 5- to 7-membered heterocycle which may optionally contain up to 2further heteroatoms and/or hetero chain members from the groupconsisting of N, O, S, SO and SO₂;

[0221] R²⁵ and R²⁶ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl,preferably hydrogen, methyl or ethyl, where (C₁-C₄)-alkyl and(C₃-C₇)-cycloalkyl for their part may optionally be substituted byhydroxyl or (C₁-C₆)-alkoxy.

[0222] Furthermore, in the compounds of the general formula (I), theradical

[0223] R² may represent one of the following groups:

[0224] A-,

[0225] A-M-,

[0226] D-M-A-,

[0227] B-M-A-,

[0228] B-,

[0229] B-M-,

[0230] B-M-B-,

[0231] D-M-B-,

[0232] where:

[0233] the radical “A” represents (C₆-CI₄)-aryl, preferably(C₆-C₁₀)-aryl, in particular phenyl or naphthyl, very particularlypreferably phenyl;

[0234] the radical “B” represents a 5- or 6-membered aromaticheterocycle which contains up to 3 heteroatoms and/or hetero chainmembers, in particular up to 2 heteroatoms and/or hetero chain members,from the group consisting of S, N, NO (N-oxide) and O;

[0235] the radical “D” represents a saturated or partially unsaturated4- to 7-membered heterocycle which contains up to three heteroatomsand/or hetero chain members from the group consisting of S, SO, SO₂, N,NO (N-oxide) and O;

[0236] the radical “M” represents —NH—, —CH₂—, —CH₂CH₂—, —O—, —NH—CH₂—,—CH₂—NH—, —OCH₂—, —CH₂O—, —CONH—, —NHCO—, —COO—, —OOC—, —S— orrepresents a covalent bond;

[0237] where

[0238] the groups “A”, “B” and “D” defined above may in each caseoptionally be mono- or polysubstituted by a radical from the groupconsisting of halogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl;pyridyl; (C₁-C₆)-alkanoyl; (C₃-C₇)-Cycloalkanoyl; (C₆-C₁₄)-aiylcarbonyl;(C₅-C₁₀)-heteroarylcarbonyl; (C₁-C₆)-alkanoyloxymethyloxy; —COOR²⁷;—SO₂R²⁷; —C(NR²⁷R²⁸)═NR²⁹; —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹; —OR³⁰; —NR³⁰R³¹,(C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl,

[0239] where (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl for their part mayoptionally be substituted by a radical from the group consisting ofcyano; —OR²⁷; —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸) and —C(NR²⁷R²⁸)═NR²⁹,

[0240] where:

[0241] v is either 0 or 1 and

[0242] R²⁷, R²⁸ and R²⁹ are identical or different and independently ofone another each represents hydrogen, (C₁-C₄)-alkyl or(C₃-C₇)-cycloalkyl and/or

[0243] R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom towhich they are attached form a saturated or partially unsaturated 5- to7-membered heterocycle having up to three, preferably up to two,identical or different heteroatoms from the group consisting of N, O andS, and

[0244] R³⁰ and R³¹ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₁-C₄)-alkyl-sulphonyl, (C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl,di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, (C₁-C₄)-alkanoyl,(C₆-C₁₄)-arylcarbonyl, (C₅-C₁₀)-heteroarylcarbonyl,(C₁-C₄)-alkylaminocarbonyl or —CH₂C(NR²⁷R²⁸)═NR²⁹.

[0245] Preference is also given to compounds of the general formula (I)in which the radical 6p1 R² represents one of the groups below:

[0246] A-,

[0247] A-M-,

[0248] D-M-A-,

[0249] B-M-A-,

[0250] B-,

[0251] B-M-,

[0252] B-M-B-,

[0253] D-M-B-,

[0254] where:

[0255] the radical “A” represents phenyl or naphthyl, in particularphenyl;

[0256] the radical “B” represents a 5- or 6-membered aromaticheterocycle which contains up to 2 heteroatoms from the group consistingof S, N, NO (N-oxide) and O;

[0257] the radical “D” represents a saturated or partially unsaturated5- or 6-membered heterocycle which contains up to two heteroatoms and/orhetero chain members from the group consisting of S, SO, SO₂, N, NO(N-oxide) and O;

[0258] the radical “M” represents —NH—, —O—, —NH—CH₂—, —CH₂—NH—, —OCH₂—,—CH₂O—, —CONH—, —NHCO— or represents a covalent bond;

[0259] where

[0260] the groups “A”, “B” and “D” defined above may in each caseoptionally be mono- or polysubstituted by a radical from the groupconsisting of halogen; trifluoromethyl; oxo; cyano; pyridyl;(C₁-C₃)-alkanoyl; (C₆-C₁₀)-arylcarbonyl; (C₅-C₆)-heteroarylcarbonyl;(C₁-C₃)-alkanoyloxymethyloxy; —C(NR²⁷R²⁸)═NR²⁹; —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹;—OH; —NR³⁰R³¹; (C₁-C₄)—, alkyl; and cyclopropyl, cyclopentyl orcyclohexyl,

[0261] where (C₁-C₄)-alkyl and cyclopropyl, cyclopentyl or cyclohexylfor their part may optionally be substituted by a radical from the groupconsisting of cyano; —OH; —OCH₃; —NR²⁸R²⁹; —CO(NH)_(v)(NR²⁷R²⁸) and—C(NR²⁷R²⁹)═NR²⁹,

[0262] where:

[0263] v is either 0 or 1, preferably 0, and

[0264] R²⁷, R²⁸ and R²⁹ are identical or different and independently ofone another each represents hydrogen, (C₁-C₄)-alkyl or else cyclopropyl,cyclopentyl or cyclohexyl and/or

[0265] R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom towhich they are attached may form a saturated or partially unsaturated 5-to 7-membered heterocycle having up to two identical or differentheteroatoms from the group consisting of N, O and S, and

[0266] R³⁰ and R³¹ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl, cyclopropyl,cyclopentyl, cyclohexyl, (C₁-C₄)-alkylsulphonyl, (C₁-C₄)-hydroxyalkyl,(C₁-C₄)-aminoalkyl, di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl,(C₁-C₃)-alkanoyl or phenylcarbonyl.

[0267] Likewise, in the compounds of the general formula (I), theradical

[0268] R² may represent a group of the following formula:

[0269] R³² represents hydrogen or (C₁-C₄)-alkyl, preferably hydrogen ormethyl, and

[0270] W represents S, NH or O, preferably S.

[0271] Moreover, in the compounds of the general formula (I), theradical

[0272] R² may be a group of the formula below

[0273] Finally, in the compounds of the general formula (I), the radical

[0274] R² may be a group of the formula below

[0275] To date, oxazolidinones have essentially only been described asantibiotics, and in individual cases also as MAO inhibitors andfibrinogen antagonists (review: Riedl, B., Endermann, R., Exp. Opin.Ther. Patents 1999, 9 (5), 625), where a small 5-[acyl-aminomethyl]group (preferably 5-[acetylaminomethyl]) appears to be essential for theantibacterial activity.

[0276] Substituted aryl- and heteroarylphenyloxazolidinones in which amono- or polysubstituted phenyl radical may be attached to the N atom ofthe oxazolidinone ring and which may have an unsubstitutedN-methyl-2-thiophenecarboxamide radical in the 5-position of theoxazolidinone ring, and their use as antibacterial substances, are knownfrom U.S. Pat. Nos. 5,929,248, 5,801,246, 5,756,732, 5,654,435,5,654,428 and 5,565,571.

[0277] In addition, benzamidine-containing oxazolidinones are known assynthetic intermediates in the synthesis of factor Xa inhibitors and/orfibrinogen antagonists (WO-A-99/31092, EP-A-623615).

[0278] Depending on the substitution pattern, the compounds of thegeneral formula (I) according to the invention may exist instereoisomeric forms which are either like image and mirror image(enantiomers) or not like image and mirror image (diastereomers). Theinvention relates both to the enantiomers or diastereomers and to theirrespective mixtures. The racemic forms, like the diastereomers, can beseparated in a known manner into the stereoisomerically uniformcomponents.

[0279] Furthermore, certain compounds of the general formula (I) can bepresent in tautomeric forms. This is known to the person skilled in theart, and such compounds are likewise within the scope of the invention.

[0280] Physiologically acceptable, i.e. pharmaceutically compatible,salts can be salts of the compounds according to the invention withinorganic or organic acids. Preference is given to salts with inorganicacids, such as, for example, hydrochloric acid, hydrobromic acid,phosphoric acid or sulphuric acid, or to salts with organic carboxylicor sulphonic acids, such as, for example, acetic acid, trifluoroaceticacid, propionic acid, maleic acid, fumaric acid, malic acid, citricacid, tartaric acid, lactic acid, benzoic acid, or methanesulphonicacid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acidor naphthalenedisulphonic acid.

[0281] Other pharmaceutically compatible salts which may be mentionedare salts with customary bases, such as, for example, alkali metal salts(for example sodium or potassium salts), alkaline earth metal salts (forexample calcium or magnesium salts) or ammonium salts, derived fromammonia or organic amines, such as, for example, diethylamine,triethylamine, ethyldiisopropylamine, procaine, dibenzylamine,N-methylmorpholine, dihydroabietylamine or methylpiperidine.

[0282] According to the invention, “hydrates” are forms of the compoundsof the general formula (I) above which form a molecule compound(solvate) in the solid or liquid state by hydration with water. In thehydrates, the water molecules are attached through secondary valenciesby intermolecular forces, in particular hydrogen bridges. Solid hydratescontain water as soalled crystal water in stoichiometric ratios, wherethe water molecules do not have to be equivalent with respect to theirbinding state. Examples of hydrates are sesquihydrates, monohydrates,dihydrates or trihydrates. Equally suitable are the hydrates of salts ofthe compounds according to the invention.

[0283] According to the invention, “prodrugs” are forms of the compoundsof the general formula (I) above which for their part can bebiologically active or inactive, but which can be converted into thecorresponding biologically active form (for example metabolically,solvolytically or in another way).

[0284] Halogen represents fluorine, chlorine, bromine and iodine.Preference is given to chlorine or fluorine.

[0285] (C₁-C₈)-Alkyl represents a straight-chain or branched alkylradical having 1 to 8 carbon atoms. Examples which may be mentioned are:methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl and n-hexyl. The corresponding alkyl groups with fewer carbonatoms, such as, for example, (C₁-C₆)-alkyl and (C₁-C₄)-alkyl, arederived analogously from this definition. In general, preference isgiven to (C₁-C₄)-alkyl.

[0286] The meaning of the corresponding component of other more complexsubstituents, such as, for example, alkylsulphonyl, hydroxyalkyl,hydroxyalkylcarbonyl, alkoxyalkyl, alkoxycarbonyl-alkyl, alkanoylalkyl,aminoalkyl or alkylaminoalkyl is likewise derived from this definition.

[0287] (C₃-C₇)-Cycloalkyl represents a cyclic alkyl radical having 3 to7 carbon atoms. Examples which may be mentioned are: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The correspondingcycloalkyl groups having fewer carbon atoms, such as, for example,(C₃-C₅)-cycloalkyl, are derived analogously from this definition.Preference is given to cyclopropyl, cyclopentyl and cyclohexyl.

[0288] The meaning of the corresponding component of other more complexsubstituents, such as, for example, cycloalkanoyl, is likewise derivedfrom this definition.

[0289] In the context of the invention, (C₂-C₆)-alkenyl represents astraight-chain or branched alkenyl radical having 2 to 6 carbon atoms.Preference is given to a straight-chain or branched alkenyl radicalhaving 2 to 4 carbon atoms. Examples which may be mentioned are: vinyl,allyl, isopropenyl and n-but-2-en-1-yl.

[0290] (C₁-C₈)-Alkoxy represents a straight-chain or branched alkoxyradical having 1 to 8 carbon atoms. Examples which may be mentioned are:methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and n-octoxy. Thecorresponding alkoxy groups having fewer carbon atoms, such as, forexample, (C₁-C₆)-alkoxy and (C₁-C₄)-Alkoxy, are derived analogously fromthis definition. In general, preference is given to (C₁-C₄)-alkoxy.

[0291] The meaning of the corresponding component of other more complexsubstituents, such as, for example alkoxy-alkyl, alkoxycarbonyl-alkyland alkoxycarbonyl, is likewise derived from this definition.

[0292] Mono- or di-(C₁-C₄)-alkvlaminocarbonyl represents an amino groupwhich is attached via a carbonyl group and which has a straight-chain orbranched or two identical or different straight-chain or branched alkylsubstitutents having in each case 1 to 4 carbon atoms. Examples whichmay be mentioned are: methylamino, ethylamino, n-propylamino,isopropylamino, t-butylamino, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino and N-t-butyl-N-methylamino.

[0293] (C₁-C₆)-Alkanoyl represents a straight-chain or branched alkylradical having 1 to 6 carbon atoms which carries a doubly attachedoxygen atom in the 1-position and is attached via the 1-position.Examples which may be mentioned are: formyl, acetyl, propionyl,n-butyryl, i-butyryl, pivaloyl, n-hexanoyl. The corresponding alkanoylgroups with fewer carbon atoms, such as, for example, (C₁-C₅)-alkanoyl,(C₁-C₄)-alkanoyl and (C₁-C₃)-alkanoyl, are derived analogously from thisdefinition. In general, preference is given to (C₁-C₃)-alkanoyl.

[0294] The meaning of the corresponding component of other more complexsubstituents, such as, for example, cycloalkanoyl and alkanoylalkyl, islikewise derived from this definition.

[0295] (C₃-C₇)-Cycloalkanoyl represents a cycloalkyl radical having 3 to7 carbon atoms as, defined above which is attached via a carbonyl group.

[0296] (C₁-C₆)-Alkanoyloxymethyloxy represents a straight-chain orbranched alkanoyloxymethyloxy radical having 1 to 6 carbon atoms.Examples which may be mentioned are: acetoxymethyloxy,propionoxymethyloxy, n-butyroxymethyloxy, i-butyroxymethyloxy,pivaloyloxymethyloxy, n-hexanoyloxymethyloxy. The correspondingalkanoyloxymethyloxy groups having fewer carbon atoms, such as, forexample, (C₁-C₃)-alkanoyloxymethyloxy, are derived analogously from thisdefinition. In general, preference is given to(C₁-C₃)-alkanoyloxymethyloxy.

[0297] (C₆-C₁₄)-Aryl represents an aromatic radical having 6 to 14carbon atoms. Examples which may be mentioned are: phenyl, naphthyl,phenanthrenyl and anthracenyl. The corresponding aryl groups with fewercarbon atoms, such as, for example, (C₆-C₁₀)-aryl are derivedanalogously from this definition. In general, preference is given to(C₆-C₁₀)-aryl.

[0298] The meaning of the corresponding component of other more complexsubstituents, such as, for example, arylcarbonyl, is likewise derivedfrom this definition.

[0299] (C₅-C₁₀)-Heteroaryl or a 5- to 10-membered aromatic heterocyclehaving up to 3 heteroatoms and/or hetero chain members from the gxoupconsisting of S, O, N and NO (N-oxide) represents a mono- or bicyclicheteroaromatic which is attached via a carbon ring atom of theheteroaromatic or, if appropriate, via a nitrogen ring atom of theheteroaromatic. Examples which may be mentioned are: pyridyl, pyridylN-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl,indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl,isoquinolyl, naphthyridinyl, quinazolinyl. The correspondingheterocycles having a smaller ring size, such as, for example, 5- or6-membered aromatic heterocycles, are derived analogously from thisdefinition. In general, preference is given to 5- or 6-membered aromaticheterocycles, such as, for example, pyridyl, pyridyl N-oxide, pyrimidyl,pyridazinyl, furyl and thienyl.

[0300] The meaning of the corresponding component of other more complexsubstituents, such as, for example, (C₅-C₁₀)-heteroarylcarbonyl, islikewise derived from this definition.

[0301] A 3- to 9-membered saturated or partially unsaturated, mono- orbicyclic, optionally benzo-fused heterocycle having up to 3 heteroatomsand/or hetero chain members from the group consisting of S, SO, SO₂, N,NO (Nxide) and O represents a heterocycle which may contain one or moredouble bonds, which may be mono- or bicyclic, to which a benzene ringmay be fused to two adjacent carbon ring atoms and which is attached viaa carbon ring atom or a nitrogen ring atom. Examples which may bementioned are: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl,morpholinyl N-oxide, thiomorpholinyl, azepinyl, 1,4-diazepinyl andcyclohexyl. Preference is given to piperidinyl, morpholinyl andpyrrolidinyl.

[0302] The corresponding cycles having a smaller ring size, such as, forexample, 5- to 7-membered cycles, are derived analogously from thisdefinition.

[0303] The present invention also provides a process for preparing thecompounds of the general formula (I) according to the invention whereeither, according to one process alternative

[0304] [A] compounds of the general formula (II)

[0305] in which

[0306] the radicals R², R³, R⁴, R⁵, R⁶ and R⁷ are each as defined above,

[0307] are reacted with carboxylic acids of the general formula (III)

[0308] in which

[0309] the radical R¹ is as defined above,

[0310] or else with the corresponding carbonyl halides, preferablycarbonyl chlorides, or else with the corresponding symmetric or mixedcarboxylic anhydrides of the carboxylic acids of the general formula(III) defined above

[0311] in inert solvents, if appropriate in the presence of anactivating or coupling agent and/or a base, to give compounds of thegeneral formula (I)

[0312] in which

[0313] the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each asdefined above,

[0314] or else according to a process alternative

[0315] [B] compounds of the general formula (IV)

[0316] in which

[0317] the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as definedabove,

[0318] are converted, using a suitable selective oxidizing agent in aninert solvent, into the corresponding epoxide of the general formula (V)

[0319] in which

[0320] the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as definedabove,

[0321] and, by reaction in an inert solvent, if appropriate in thepresence of a catalyst, with an amine of the general formula (VI)

R²—NH₂  (VI),

[0322] in which

[0323] the radical R² is as defined above,

[0324] the compounds of the general formula (VII)

[0325] in which

[0326] the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each asdefined above,

[0327] are initially prepared and

[0328] subsequently, in an inert solvent in the presence of phosgene orphosgene equivalents, such as, for example, carbonylduimidazole (CDI),cyclized to give the compounds of the general formula (I)

[0329] in which

[0330] the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each asdefined above,

[0331] where—both for process alternative [A] and for processalternative [B]—in the case where R² contains a 3- to 7-memberedsaturated or partially unsaturated cyclic hydrocarbon radical having oneor more identical or different heteroatoms from the group consisting ofN and S, an oxidation with a selective oxidizing agent to afford thecorresponding sulphone, sulphoxide or N-oxide may follow

[0332] and/or

[0333] where—both for process alternative [A] and for processalternative [B]—in the case where the compound prepared in this mannerhas a cyano group in the molecule, an amidination of this cyano group bycustomary methods may follow

[0334] and/or

[0335] where—both for process alternative [A] and for processalternative [B]—in the case where the compound prepared in this mannerhas a BOC amino protective group in the molecule, removal of this BOCamino protective group by customary methods may follow

[0336] and/or

[0337] where—both for process alternative [A] and for processalternative [B]—in the case where the compound prepared in this mannerhas an aniline or benzylamine radical in the molecule, a reaction ofthis amino group with various reagents such as carboxylic acids,carboxylic anhydrides, carbonyl chlorides, isocyanates, sulphonylchlorides or alkyl halides to give the corresponding derivatives mayfollow

[0338] and/or

[0339] where—both for process alternative [A] and for processalternative [B]—in the case where the compound prepared in this mannerhas a phenyl ring in the molecule, a reaction with chlorosulphonic acidand subsequent reaction with amines to give the correspondingsulphonamides may follow.

[0340] The processes according to the invention can be illustrated in anexemplary manner by the equations below:

[0341] The oxidation step described above, which is optional, can beillustrated in an exemplary manner by the equation below:

[0342] Suitable solvents for the processes described above are organicsolvents which are inert under the reaction conditions. These includehalogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, 1,2-dichloroethane, trichloroethane,tetrachloroethane, 1,2-dichloroethylene or trichloroethylene, ethers,such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl etheror diethylene glycol dimethyl ether, alcohols, such as methanol,ethanol, n-propanol, isopropanol, n-butanol or tert-butanol,hydrocarbons, such as benzene, xylene, toluene, hexane or cyclohexane,dimethylformamide, dimethyl sulphoxide, acetonitrile, pyridine,hexamethylphosphoric triamide or water.

[0343] It is also possible to use solvent mixtures of the solventsmentioned above.

[0344] Suitable activating or coupling agents for the processesdescribed above are the reagents which are customarily used for thispurpose, for example N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide·HCl,N,N′-dicyclohexylcarbodiimide, 1-hydroxy-1H-benzotriazole·H₂O and thelike.

[0345] Suitable bases are the customary inorganic or organic bases.These preferably include alkali metal hydroxides, such as, for example,sodium hydroxide or potassium hydroxide, or alkali metal carbonates,such as sodium carbonate or potassium carbonate, or sodium methoxide orpotassium methoxide or sodium ethoxide or potassium ethoxide orpotassium-tert-butoxide, or amides, such as sodium amide, lithiumbis-(trimethylsilyl)amide or lithium diisopropylamide, or amines, suchas triethylamine, diisopropylethylamine, diusopropylamine,4-N,N-dimethylaminopyridine or pyridine.

[0346] The base can be employed here in an amount of from 1 to 5 mol,preferably from 1 to 2 mol, based on 1 mol of the compounds of thegeneral formula (II).

[0347] The reactions are generally carried out in a temperature range offrom −78° C. to reflux temperature, preferably in the range from 0° C.to reflux temperature.

[0348] The reactions can be carried out at atmospheric, elevated orreduced pressure (for example in the range from 0.5 to 5 bar). Ingeneral, the reactions are carried out at atmospheric pressure.

[0349] Suitable selective oxidizing agents, both for the preparation ofthe epoxides and for the optional oxidation to give the sulphone,sulphoxide or N-oxide, are m-chloroperbenzoic acid (MCPBA), sodiummetaperiodate, N-methylmorpholine N-oxide (NMO), monoperoxyphthalic acidor osmium tetroxide.

[0350] With respect to the preparation of the epoxides, the preparationconditions which are customary for this purpose are employed.

[0351] With respect to more detailed process conditions for the optionaloxidation to give the sulphone, sulphoxide or N-oxide, reference is madeto the following literature: M. R. Barbachyn et al., J. Med. Chem. 1996,39, 680 and WO-A-97/10223.

[0352] Furthermore, reference is made to Examples 14 to 16 given in theexperimental part.

[0353] The optional arnidation is carried out under customaryconditions. For more details, reference is made to Examples 31 to 35 and140 to 147.

[0354] The compounds of the general formulae (II), (III), (IV) and (VI)are known per se to the person skilled in the art or can be prepared bycustomary methods. For oxazolidinones, in particular the5-(aminomethyl)-2-oxooxazolidines required, cf. WO-A-98/01446;WO-A-93/23384; WO-A-97/03072; J. A. Tucker et al., J. Med. Chem. 1998,41, 3727; S. J. Brickner et al., J. Med. Chem. 1996, 39, 673; W. A.Gregory et al., J. Med. Chem. 1989, 32, 1673.

[0355] The compounds of the general formula (a) according to theinvention have an unforeseeable useful pharmacological activity spectrumand are therefore particularly suitable for the prophylaxis and/ortreatment of disorders.

[0356] The compounds of the general formula (I) according to theivnention—including the compounds which are excluded by disclaimer fromthe chemical product protection—act in particular as anticoagulants andcan therefore preferably be employed in medicaments for the prophylaxisand/or therapy of thromboembolic disorders. For the purpose of thepresent invention, “thromboembolic disorders” include, in particular,serious disorders such as myocardial infarct, angina pectoris (includingunstable angina), reocclusions and restenoses after angioplasty oraortocoronary bypass, stroke, transitory ischaemic attacks, peripheralarterial occlusion disorders, pulmonary embolisms or deep venousthromboses.

[0357] Furthermore, the compounds of the general formula (I) accordingto the invention—including the compounds which are excluded bydisclaimer from the, chemical product protection—are also suitable fortreating disseminated intravascular coagulation (DIC).

[0358] Finally, the compounds of the general formula (I) according tothe invention—including the compounds which are excluded by disclaimerfrom the chemical product protection—are also suitable for theprophylaxis and/or treatment of atherosclerosis and arthritis, andadditionally also for the prophylaxis and/or treatment of Alzheimer'sdisease and cancer.

[0359] The compounds of the general formula (I) according to theinvention—including the compounds excluded by disclaimer from thechemical product protection—act in particular as selective inhibitors ofthe blood coagulation factor Xa and do not inhibit, or only inhibit atconsiderably higher concentrations, other serine proteases as well, suchas thrombin, plasmin or trypsin.

[0360] In the context of the present invention, inhibitors of the bloodcoagulation factor Xa in which the IC₅₀ values for the factor Xainhibition are lower by a factor of 100, preferably by a factor of 500,in particular by a factor of 1000, than the IC₅₀ values for theinhibition of other serine proteases, in particular thrombin, plasminand trypsin, are referred to as being “selective”, where with a view tothe test methods for selectivity, reference is made to the test methodsof Examples A-1) a.1) and a.2) described below.

[0361] The compounds of the general formula (I) according to theinvention—including the compounds which are excluded by disclaimer fromthe chemical product protection—can furthermore be used for preventingcoagulation ex vivo, for example for banked blood or biological sampleswhich contain factor Xa.

[0362] The present invention thus provides oxazolidinones of the formula(I) effecting in particular an unexpected, strong and selectiveinhibition of factor Xa, and this also applies to the compounds excludedby disclaimer from the chemical product protection.

[0363] The present invention further provides medicaments andpharmaceutical compositions comprising at least one compound of thegeneral formula (I) according to the invention together with one or morepharmacologically acceptable auxiliaries or excipients, whichmedicaments and pharmaceutical compositions can be used for theindications mentioned above.

[0364] Furthermore, the present invention relates to a method for theprophylaxis and/or treatment of disorders of the human or animal body,in particular of the abovementioned disorders, using the compounds ofthe general formula (I) according to the invention—including thecompounds excluded by disclaimer from the chemical product protection.

[0365] Furthermore, the present invention also includes a method forpreventing blood coagulation in vitro, in particular in banked blood orbiological samples which contain factor Xa, which method ischaracterized in that compounds of the general formula (I)—including thecompounds excluded by disclaimer from the chemical productprotection—are added.

[0366] All customary administration forms are suitable foradministration of the compounds according to the invention.Administration is preferably carried out orally, lingually,sublingually, buccally, rectally or parenterally (i.e. bypassing theintestinal tract, that is intravenously, intraarterially,intracardially, intracutaneously, subcutaneously, transdermally,intraperitoneally or intramuscularly). Particularly suitable are oraland intravenous administration. Very particular preference is given tooral administration, this being a further advantage with respect to theprior-art therapy of thromboembolic disorders.

[0367] The novel active compounds of the general formula (I) can beconverted in a known manner into the customary formulations, such astablets, sugar-coated tablets, pills, granules, aerosols, syrups,emulsions, suspensions and solutions, using inert non-toxicpharmaceutically suitable excipients or solvents. Here, thetherapeutically active compound should in each case be present in aconcentration of from about 0.1 to 95% by weight, preferably from 0.5 to90% by weight, in particular from 1 to 85% by weight, of the totalmixture, i.e. in amounts which are sufficient in order to achieve thedosage range indicated.

[0368] In spite of this, if appropriate, it may be necessary to departfrom the amounts mentioned, namely depending on the body weight or onthe type of administration route, on the individual response to themedicament, on the manner of its formulation and the time or interval atwhich administration takes place. Thus, in some cases it may be adequateto manage with less than the abovementioned minimum amount, while inother cases the upper limit mentioned must be exceeded. In the case ofthe administration of relatively large amounts, it may be advisable todivide these into several individual administrations over the course ofthe day.

[0369] The formulations are prepared, for example, by extending theactive compounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, it being possible, for example if thediluent used is water, optionally to use organic solvents as auxiliarysolvents.

[0370] In general it has proved advantageous in the case of intravenousadministration to administer amounts from approximately 0.001 to 10mg/kg, preferably approximately 0.01 to 10 mg/kg, in particularapproximately 0.1 to 8 mgtkg, of body weight to achieve effectiveresults.

[0371] In general, it has proved advantageous in the case of oraladministration to administer amounts from approximately 0.01 to 50mg/kg, preferably approximately 0.1 to 10 mg/kg, in particularapproximately 0.5 to 8 mg/kg, of body weight to achieve effectiveresults.

[0372] In spite of this, if appropriate, it may be necessary in the caseof intravenous or oral administration to depart from the amountsmentioned, namely depending on the body weight or on the type ofadministration route, on the individual response to the medicament, onthe manner of its formulation and the time or interval at whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the abovementioned mininum amount, while in othercases the upper limit mentioned must be exceeded. In the case of theadministration of relatively large amounts, it may be advisable todivide these over the course of the day, namely into several individualdoses or as a continuous infusion.

[0373] Compared to the conventional preparations for treatingthromboembolic disorders, the compounds of the general formula (I)according to the invention—including the compounds excluded bydisclaimer from the chemical product protection—are distinguished inparticular by the fact that a greater therapeutic range is achieved bythe selective inhibition of factor Xa. For the patient, this means alower risk of, bleeding, and for the treating physician, this means thatthe patient is easier to adjust. Moreover—owing to the mechanism—theonset of action is more rapid. Above all, however, the compoundsaccording to the invention permit an oral administration form, which isa further advantage of the therapy with the compounds according to theinvention.

[0374] The present invention is illustrated by the examples below;however, these examples are not meant to restrict the invention in anyway.

EXAMPLES

[0375] A Evaluation of the Physiological Activity

[0376] 1. General Test Methods

[0377] The particularly advantageous biological properties of thecompounds according to the invention can be determined by the followingmethods.

[0378] a) Test Description (In Vitro)

[0379] a.1) Determination of the Factor Xa Inhibition

[0380] The enzymatic activity of human factor Xa (FXa) was measuredusing the conversion of a chromogenic substrate specific for FXa. FactorXa cleaves p-nitroaniline from the chromogenic substrate. Thedeterminations were carried out in microtitre plates as follows.

[0381] The test substances, in various concentrations, were dissolved inDMSO and incubated at 25° C. with human FXa (0.5 nmol/l dissolved in 50mmol/l of tris buffer [C,C,C-tris(hydroxymethyl)-arninomethane], 150mmol/l of NaCl, 0.1% BSA (bovine serum albumin), pH=8.3) for 10 minutes.Pure DMSO was used as control. The chromogenic substrate (150 μmol/l ofPefachrome® FXa from Pentapharm) was then added. After an incubationtime of 20 minutes at 25° C., the extinction at 405 nm was determined.The extinctions of the test mixtures containing test substance werecompared with the control mixtures without test substance, and the IC₅₀values were calculated from these data.

[0382] a.2) Determination of the Selectivity

[0383] To assess selective FXa inhibition, the test substances wereexamined for their inhibition of other human serine proteases such asthrombin, trypsin and plasmin. To determine the enzymatic activity ofthrombin (75 mU/ml), trypsin (500 mU/ml) and plasmin (3.2 mmol/l), theseenzymes were dissolved in tris buffer (100 mmol/l, 20 mmol/l CaCl₂,pH=8.0) and incubated with test substance or solvent for 10 minutes. Theenzymatic reaction was then started by adding the corresponding specificchromogenic substrates (Chromozym Thrombin® from Boehringer Mannheim,Chromozym Trypsin® from Boehringer Mannheim, Chromozym Plasmin® fromBoehringer Mannheim) and the extinction at 405 nm was determined after20 minutes. All determinations were carried out at 37° C. Theextinctions of the test mixtures containing test substance were comparedwith the control samples without test substance, and the IC₅₀ valueswere calculated from these data.

[0384] a.3) Determination of the Anticoagulant Action

[0385] The anticoagulant action of the test substances was determined invitro in human plasma. To this end, human blood was drawn off in amixing ratio of sodium citrate/blood of {fraction (1/9)} using a 0.11molar sodium citrate solution as receiver. Immediately after the bloodhad been drawn off, it was mixed thoroughly and centrifuged at about2000 g for 10 minutes. The supernatant was pipetted off. The prothrombintime (PT, synonyms: thromboplastin time, quick test) was determined inthe presence of varying concentrations of test substance or thecorresponding solvent using a commercial test kit (Neoplastin® fromBoehringer Mannheim). The test compounds were incubated with the plasmaat 37° C. for 10 minutes. Coagulation was then started by addition ofthromboplastin, and the time when coagulation occurred was determined.The concentration of test substance which effected a doubling of theprothrombin time was determined.

[0386] b) Determination of the Antithrombotic Activity (In Vivo)

[0387] b.1) Arteriovenous Shunt Model (Rat)

[0388] Fasting male rats (strain: HSD CPB:WU) having a weight of 200-250g were anaesthetized using a Rompun/Ketavet solution (12 mg/kg/ 50mg/kg). Thrombus formation was initiated in an arteriovenous shunt inaccordance with the method described by Christopher N. Berry et al., Br.J. Pharmacol. (1994), 113, 1209-1214. To this end, the left jugular veinand the right carotid artery were exposed. The two vessels wereconnected by an extracorporeal shunt using a polyethylene tube (PE 60)of a length of 10 cm. In the middle, this polyethylene tube was attachedto a further polyethylene tube (PE 160) of a length of 3 cm whichcontained a roughened nylon thread which had been arranged to form aloop, to form a thrombogenic surface. The extracorporeal circulation wasmaintained for 15 minutes. The shunt was then removed and the nylonthread with the thrombus was weighed immediately. The weight of thenylon thread on its own had been determined before the experiment wasstarted. Before the extracorporeal circulation was set up, the testsubstances were administered to the animals while awake eitherintravenously via the tail vein or orally using a pharyngeal tube.

[0389] The results are shown in Table 1: TABLE 1 Antithrombotic activityin the arteriovenous shunt model (rat) after oral or intravenousadministration Example ED₅₀ [mg/kg]p.o. ED₅₀ [mg/kg]i.v. 1 10 17 6 44 395 3 114 3 115 3 123 3 162 3

[0390] b.2) Arteriel Thrombosis Model (Rat)

[0391] Male fasting rats (strain: HSD CPB: WU) were anaesthetized asdescribed above. On average, the rats had a weight of about 200 g. Theleft carotid artery was exposed (about 2 cm). The formation of anarterial thrombus was induced by mechanical injury to the blood vesselin accordance with the method described by K. Meng et al.,Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To thisend, the exposed carotid artery was clamped from the blood flow, cooledto −12° C. in a metal trough for 2 minutes and, to standardize the sizeof the thrombi, simultaneously compressed using a weight of 200 g. Theblood flow was then additionally reduced by a clip which was placedaround the carotid artery distally from the injured section of thevessel. The proximal clamp was removed, and the wound was closed andre-opened after 4 hours to remove the injured section of the vessel. Thesection of the vessel was opened longitudinally and the thrombus wasremoved from the injured section of the vessel. The moist weight of thethrombi was determined immediately. The test substances wereadministered to the animals while awake at the beginning of theexperiment, either intravenously via the tail vein or orally using apharyngeal tube.

[0392] b.3) Venous Thrombosis Model (Rat)

[0393] Male fasting rats (strain: HSD CPB: WU) were anaesthetized asdescribed above. On average, the rats had a weight of about 200 g. Theleft jugular vein was exposed (about 2 cm). The formation of a venousthrombus was induced by mechanical injury to the blood vessel inaccordance with the method described by K. Meng, et al.,Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To thisend, the jugular vein was clamped from the blood flow, cooled to −12° C.in a metal trough for 2 minutes and, to standardize the size of thethrombi, simultaneously compressed using a weight of 200 g. The bloodflow was re-opened and the wound was closed. After 4 hours, the woundwas re-opened to remove the thrombi from the injured sections of thevessel. The moist weight of the thrombi was determined immediately. Thetest substances were administered to the animals while awake at thebeginning of the experiment, either intravenously via the tail vein ororally using a pharyngeal tube.

B Preparation Examples

[0394] Starting Materials

[0395] The preparation of 3-morpholinone is described in U.S. Pat. No.5,349,045.

[0396] The preparation of N-(2,3-epoxypropyl)phthalimide is described inJ. -W. Chern et al. Tetrahedron Lett. 1998,39,8483.

[0397] The substituted anilines can be obtained by reacting, forexample, 4-fluoronitrobenzene, 2,4-difluoronitrobenzene or4-chloronitrobenzene with the appropriate amines or amides in thepresence of a base. This can also be carried out using Pd catalysts,such as Pd(OAc)₂/DPPF/NaOt-Bu (Tetrahedron Lett. 1999,40,2035) or copper(Renger, Synthesis 1985,856; Aebischer et al., Heterocycles1998,48,2225). Likewise, it is possible to initially convert halogenatedaromatics without nitro group into the corresponding amides, followed bynitration in the 4-position (U.S. Pat. No. 3,279,880).

[0398] I. 4-(4-Morpholin-3-onyl)Nitrobenzene

[0399] 2 mol (202 g) of morpholin-3-one (E. Pfeil, U. Harder, Angew.Chem. 79, 1967, 188) are dissolved in 2 l of N-methylpyrrolidone (NNP).Over a period of 2 h, 88 g (2.2 mol) of sodium hydride (60% in paraffin)are then added a little at a time. After the evolution of hydrogen hasceased, 282 g (2 mol) of 4-fluoronitrobenzene are added dropwise withcooling at room temperature, over a period of 1 h, and the reactionmixture is then stirred ovemight. At 12 mbar and 76° C., 1.7 1 of theliquid volume are then distilled off, the residue is poured into 2 l ofwater and this mixture is extracted twice with in each case 1 l of ethylacetate. After washing of the combined organic phases with water, themixture is dried over sodium sulphate and the solvent is distilled offunder reduced pressure. Purification is carried out by silica gelchromatography using hexanelethyl acetate (1:1) and subsequentcrystallization from ethyl acetate. This gives 78 g of product as acolourless to brownish solid, in a yield of 17.6% of theory.

[0400]¹H-NMR (300 MHz, CDCl₃): 3.86 (m, 2 H, CH₂CH₂), 4.08 (m, 2 H,CH₂CH₂), 4.49 (s, 2H, CH₂CO), 7.61 (d, 2 H, ³J=8.95 Hz, CHCH), 8.28 (d,2H, ³J=8.95 Hz, CHCH)

[0401] MS (r.I. %)=222 (74, M⁺), 193 (100), 164 (28), 150 (21), 136(61), 117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50 (25)

[0402] The following compounds were synthesized analogously:

[0403] 3-fluoro4-(4-morpholin-3-onyl)nitrobenzene

[0404] 4-(N-piperidonyl)nitrobenzene

[0405] 3-fluoro-4-(N-piperidonyl)nitrobenzene

[0406] 4(N-pyrrolidonyl)nitrobenzene

[0407] 3-fluoro4-(N-pyrrolidonyl)nitrobenzene

[0408] II. 4-(4-Morpholin-3-onyl)Aniline

[0409] In an autoclave, 63 g (0.275 mol) of4-(4-morpholin-3-onyl)nitrobenzene are dissolved in 200 ml oftetrahydrofuran, admixed with 3.1 g of Pd/C (5% ig) and hydrogenated at70° C. and a hydrogen pressure of 50 bar for 8 h. The catalyst isfiltered off, the solvent is then distilled off under reduced pressureand the product is purified by crystallization from ethyl acetate. 20 gof product are obtained as a colourless to bluish solid, in a yield of37.6% of theory.

[0410] Purification can also be carried out by silica gel chromatographyusing hexane/ethyl acetate.

[0411]¹H-NMR (300 MHz, CDCl₃): 3.67 (m, 2 H, CH₂CH₂), 3.99 (m, 2 H,CH₂CH₂), 4.27 (s, 2 H, CH₂CO), 6.68 (d, 2 H, ³J=8.71 Hz, CHCH), 7.03 (d,2 H, ³J=8.71 Hz, CHCH)

[0412] MS (r.I. %)=192 (100, M⁺), 163 (48), 133 (26), 119 (76), 106(49), 92 (38), 67 (27), 65 (45), 52 (22), 28 (22)

[0413] The following compounds were synthesized analogously:

[0414] 3-fluoro4-(4-morpholin-3-onyl)aniline

[0415] 4-(N-piperidonyl)aniline

[0416] 3-fluoro4-(N-piperidonyl)aniline

[0417] 4-(N-pyrrolidonyl)aniline

[0418] 3-fluoro4(N-pyrrolidonyl)aniline

[0419] General method for preparing 4-substituted anilities by reacting1-fluoro-4-nitrobenzenes and 1-chloro-4nitrobenzenes with primary orsecondary amines, followed by reduction

[0420] Equimolar amounts of the fluoronitrobenzene or chloronitrobenzeneand the amine are dissolved in dimethyl sulphoxide or acetonitrile (0.1M to 1 M solution), and the mixture is stirred at 100° C. overnight.After cooling to RT, the reaction mixture is diluted with ether andwashed with water. The organic phase is dried over MgSO₄, filtered andconcentrated. If a precipitate forms in the reaction mixture, theprecipitate is filtered off and washed with ether or acetonitrile. Ifthe mother liquor also contains product, it is worked up as describedusing ether and water. The crude products can be purified by silica gelchromatography (dichloromethane/cyclohexane and dichloromethane/ethanolmixtures).

[0421] For the subsequent reduction, the nitro compound is dissolved inmethanol, ethanol or ethanol/dichloromethane mixtures (0.01 M to 0.5 Msolution) admixed with palladium on carbon (10%) and stirred under anatmospheric hydrogen pressure overnight. The mixture is then filteredand concentrated. The crude product can be purified by silica gelchromatography (dichloromethane/ethanol mixtures) or preparativereversed-phase HPLC (acetonitrile/water mixtures).

[0422] Alternatively, the reducing agent used can also be iron powder.To this end, the nitro compound is dissolved in acetic acid (0.1 M to0.5 M solution) and, at 90° C., six equivalents of iron powder and water(0.3 to 0.5 times the volume of the acetic acid) are added a little at atime over a period of 10-15 min. After a further 30 min at 90° C., themixture is filtered and the filtrate is concentrated. The residue isworked up by extraction with ethyl acetate and 2N aqueous sodiumhydroxide solution. The organic phase is dried over magnesium sulphate,filtered and concentrated. The crude product can be purified by silicagel chromatography (dichloromethane/ethanol mixtures) or preparativereversed-phase HPLC (acetonitrile/water mixtures).

[0423] The following starting materials were prepared in an analogousmanner:

[0424] III-1. tert-butyl-1-(4-aminophenyl)-L-prolinate

[0425] MS (ESI): m/z (%)=304 (M+H+MeCN, 100), 263 (M+H, 20);

[0426] HPLC (method 4): rt=2.79 min.

[0427] III-2. 1-(4-aminophenyl)-3-piperidinecarboxamide

[0428] MS (ESI): m/z (%)=220 (M+H, 100);

[0429] HPLC (method 4): rt=0.59 min.

[0430] III-3. 1-(4-aminophenyl)-4-piperidincarboxamide

[0431] MS (ESI): m/z (%)=220 (M+H, 100);

[0432] HPLC (method 4): rt=0.57 min.

[0433] III-4. 1-(4-aminophenyl)-4-piperidinone

[0434] MS (ESI): m/z (%)=191 (M+H, 100);

[0435] HPLC (method 4): rt=0.64 min.

[0436] III-5. 1-(4-aminophenyl)-L-prolinamide

[0437] MS (ESI): m/z (%)=206 (M+H, 100);

[0438] HPLC (method 4): rt=0.72 min.

[0439] III-6. [1-(4-aminophenyl)-3-Diperidinyl]methanol

[0440] MS (ESI): m/z (%)=207 (M+H, 100);

[0441] HPLC (method 4): rt=0.60 min.

[0442] III-7. [1-(4-aminophenyl)-2-piperidinyl]methanol

[0443] MS (ESI): m/z (%)=207 (M+H, 100);

[0444] HPLC (method 4): rt=0.59 min.

[0445] III-8. ethyl 1-(4-aminophenyl)-2-piperidinecarboxylate

[0446] MS (ESI): m/z (%)=249 (M+H, 35), 175 (100);

[0447] HPLC (method 4): rt=2.43 min.

[0448] III-9. [1-(4-aminophenyl)-2-pyrrolidinyl]methanol

[0449] MS (ESI): m/z (%)=193 (M+H, 45);

[0450] HPLC (method 4): rt=0.79 min.

[0451] III-10.4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl)phenylamine startingfrom 2-methylhexahydro-2H-pyrrolo[3,4-d]isoxazole (Ziegler, Carl B., etal.; J. Heterocycl. Chem.; 25; 2; 1988; 719-723)

[0452] MS (ESI): m/z (%)=220 (M+H, 50), 171 (100);

[0453] HPLC (method 4): rt=0.54 min.

[0454] III-11. 4-(1-pyrrolidinyl)-3-(trifluoromethyl)aniline

[0455] MS (ESI): m/z (%)=231 (M+H, 100);

[0456] HPLC (method 7): rt=3.40 min.

[0457] III-12. 3-chloro-4-(1-Pyrrolidinyl)aniline

[0458] MS (ESI): m/z (%)=197 (M+H, 100);

[0459] HPLC (method 4): rt=0.78 min.

[0460] III.-13. 5-amino-2-(4-morpholinyl)benzamide

[0461] MS (ESI): m/z (%)=222 (M+H, 100);

[0462] HPLC (method 4): rt=0.77 min.

[0463] III-14. 3-methoxy-4-(4-morpholinyl)aniline

[0464] MS (ESI): m/z (%)=209 (M+H, 100);

[0465] HPLC (method 4): rt=0.67 min.

[0466] III-15. 1-[5-amino-2-(4-morpholinyl)phenyl]ethanone

[0467] MS (ESI): m/z (%)=221 (M+H, 100);

[0468] HPLC (method 4): rt=0.77 min.

[0469] General method for preparing 4-substituted anilines by reacting1-fluoro4-nitrobenzenes with amides, followed by reduction

[0470] The amide is dissolved in DMF and admixed with 1.5 equivalents ofpotassium tert-butoxide. The mixture is stirred at RT for 1 h, and 1.2equivalents of the 1-fluoro4-nitrobenzene are then added a little at atime. The reaction mixture is stirred at RT ovemight, diluted with etheror ethyl acetate and washed with sat. aqu. sodium bicarbonate solution.The organic phase is dried over magnesium sulphate, filtered andconcentrated. The crude product can be purified by silica gelchromatography (dichloromethane/ethanol mixtures).

[0471] For the subsequent reduction, the nitro compound is dissolved inethanol (0.01 M to 0.5 M solution), admixed with palladium on carbon(10%) and stirred under atmospheric hydrogen pressure overnight. Themixture is then filtered and concentrated. The crude product can bepurified by silica gel chromatography (dichloromethane/ethanol mixtures)or preparative reversed-phase BPLC (acetonitrile/water mixtures).

[0472] Alternatively, the reducing agent used can also be iron powder.To this end, the nitro compound is dissolved in acetic acid (0.1 M to0.5 M solution) and, at 90° C., six equivalents of iron powder and water(0.3 to 0.5 times the volume of the acetic acid) are added a little at atime over a period of 10-15 min. After a further 30 min at 90° C, themixture is filtered and the filtrate is concentrated. The residue isworked up by extraction with ethyl acetate and 2N aqueous sodiumhydroxide solution. The organic phase is dried over magnesium sulphate,filtered and concentrated. The crude product can be purified by silicagel chromatography (dichloromethane/ethanol mixtures) or preparativereversed-phase HPLC (acetonitrile/water mixtures).

[0473] The following starting materials were prepared in an analogousmanner:

[0474] IV-1. 1-[4-amino-2-(trifluoromethyl)phenyl]-2-pyrrolidinone

[0475] MS (ESI): m/z (%)=245 (M+H, 100);

[0476] HPLC (method 4): rt=2.98 min

[0477] IV-2. 4-[4-amino-2-(trifluoromethyl)phenyl]-3-morpholinone

[0478] MS (ESI): m/z (%)=261 (M+H, 100);

[0479] HPLC (method 4): rt=2.54 min.

[0480] IV-3. 4-(4-amino-2-chlorophenyl)-3-morpholinone

[0481] MS (ESI): m/z (%)=227 (M+H, 100);

[0482] HPLC (method 4): rt=1.96 min.

[0483] IV-4. 4-(4-amino-2-methylphenyl)-3-morpholinone

[0484] MS (ESI): m/z (%)=207 (M+H, 100);

[0485] HPLC (method 4): rt=0.71 min.

[0486] IV-5. 5-amino-2-(3-oxo-4-morpholinyl)benzonitrile

[0487] MS (ESI): m/z (%)=218 (M+H, 100);

[0488] HPLC (method 4): rt=1.85 min.

[0489] IV-6. 1-(4-amino-2-chlorophenyl)-2-pyrrolidinone

[0490] MS (ESI): m/z (%)=211 (M+H, 100);

[0491] HPLC (method 4): rt=2.27 min.

[0492] IV-7. 4-(4-amino-2,6-dimethylphenyl)-3-morpholinone

[0493] starting from 2-fluoro-1,3-dimethyl-5-nitrobenzene (Bartoli etal., J. Org. Chem. 1975, 40, 872):

[0494] MS (ESI): m/z (%)=221 (M+H, 100);

[0495] HPLC (method 4): rt=0.77 min.

[0496] IV-8. 4-(2,4-diaminophenyl)-3-morpholinone

[0497] starting from 1-fluoro-2,4dinitrobenzene:

[0498] MS (ESI): m/z (%)=208 (M+H, 100);

[0499] HPLC (method 4): rt=0.60 min.

[0500] IV-9. 4-(4-amino-2-chlorophenyl)-2-methyl-3-morpholinone

[0501] starting from 2-methyl-3-morpholinone (Pfeil, E.; Harder, U.;Angew. Chem. 1967, 79, 188):

[0502] MS (ESI): m/z (%)=241 (M+H, 100);

[0503] HPLC (method 4): rt=2.27 min.

[0504] IV-10. 4-(4-amino-2-chlorophenyl)-6-methyl-3-morpholinone

[0505] starting from 6-methyl-3-morpholinone (EP 350 002):

[0506] MS (ESI): m/z (%)=241 (M+H, 100);

[0507] HPLC (method 4): rt=2.43 min.

Synthesis Examples

[0508] The Examples 1 to 13, 17 to 19 and 36 to 57 below refer toprocess variant [A].

Example 1 Preparation of5-chloro-N-{[(SS)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

[0509]

[0510] (5S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolidin-2-one (preparation see S. J. Brickner et al., J. Med.Chem. 1996, 39, 673) (0.45 g, 1.52 mmol), 5-chlorothiophene-2-carboxylicacid (0.25 g, 1.52 mmol) and 1-hydroxy-1H-benzotriazole hydrate (HOBT)(0.3 g, 1.3 equivalents) are dissolved in 9.9 ml of DMF. 0.31 g (1.98mmol, 1.3 equivalents) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide(EDCI) are added, and 0.39 g (0.53 ml, 3.05 mmol, 2 equivalents) ofdiisopropylethylamine (DIEA) are added dropwise at room temperature. Themixture is stirred at room temperature overnight. 2 g of silica gel areadded, and the mixture is evaporated to dryness under reduced pressure.The residue is chromatographed on silica gel using a toluene/ethylacetate gradient. This gives 0.412 g (61.5% of theory) of the targetcompound of melting point (m.p.) 197° C.

[0511] R_(f) (SiO₂, toluene/ethyl acetate 1:1)=0.29 (startingmaterial=0.0);

[0512] MS (DCI) 440.2 (M+H), Cl pattern;

[0513]¹H-NMR (d₆-DMSO, 300 MHz) 2.95 (m, 4H), 3.6 (t, 2H), 3.72 (m, 4H),3.8 (dd, 1H), 4.12 (t, 1H), 4.75-4.85 (m, 1H), 7.05 (t, 1H), 7.15-7.2(m, 3H), 7.45 (dd, 1H), 7.68 (d, 1H), 8.95 (t, 1H).

Example 25-Chloro-N-{[(5S)-3-(4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

[0514]

[0515] is obtained analogously from benzyl 4-morpholinophenylcarbamatevia the(5S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolidin-2-oneintermediate (see Example 1).

[0516] M.p.: 198° C.;

[0517] IC₅₀ value=43 nM;

[0518] R_(f) (SiO₂, toluene/ethyl acetate 1:1)=0.24.

Example 35-Chloro-N-({(5S)-3-[3-fluoro-4-(1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0519]

[0520] is obtained analogously from(5S)-5-(aminomethyl)-3-[3-fluoro4-(1,4-thiazinan4-yl)phenyl]-1,3-oxazolidin-2-one(preparation see M. R. Barbachyn et al., J. Med. Chem. 1996, 39, 680).

[0521] M.p.: 193° C.;

[0522] Yield: 82%;

[0523] R_(f) (SiO₂, toluene/ethyl acetate 1:1)=0.47 (startingmaterial=0.0).

Example 4 5-Bromo-N-({(5S)-3-[3-fluoro-4-(1,4-thiazinanyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0524]

[0525] is obtained analogously from 5-bromothiophene-2-carboxylic acid.

[0526] M.p.: 200° C.

Example 5N-({(5S)-3-[3-Fluoro-4-(1,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-methyl-2-thiophenecarboxamide

[0527]

[0528] is obtained analogously from 5-methylthiophene-2-carboxylic acid.

[0529] M.p.: 167° C.

Example 65-Chloro-N-{[(5S)-3-(6-methylthieno[2,3-b]pyridin-2-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

[0530]

[0531] is obtained analogously from(5S)-5-(aminomethyl)-3-(6-methylthieno[2,3-b]pyridin-2-yl)-1,3-oxazolidin-2-one(preparation see EP-A-785 200).

[0532] M.p.: 247° C.

Example 75-Chloro-N-{[(5S)-3-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

[0533]

[0534] is obtained analogously from6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-methyl-1,3-benzothiazol-2(3H)-one(preparation see EP-A-738 726).

[0535] M.p.: 217° C.

Example 85-Chloro-N-[((5S)-3-{3-fluoro-4-[4-(4-pyridinyl)piperazino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0536]

[0537] is obtained analogously from(5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(4-pyridinyl)piperazino]phenyl}-1,3-oxazolidin-2-one(preparation analogously to J. A. Tucker et al., J. Med. Chem. 1998, 41,3727).

[0538] MS (ESI) 516 (M+H), Cl pattern.

Example 95-Chloro-N-({(5S)-3-[3-fluoro-4-(4-methylpiperazino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0539]

[0540] is obtained analogously from(5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-methylpiperazino)phenyl]-1,3-oxazolidin-2-one.

Example 105-Chloro-N-({(5S)-3-[3-fluoro-4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0541]

[0542] is obtained analogously from(5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-tert-butoxy-carbonylpiperazin-1-yl)phenyl]-1,3-oxazolidin-2-one(preparation see WO-A-93/23384, which has already been cited).

[0543] M.p.: 184° C.;

[0544] R_(f) (SiO₂, toluene/ethyl acetate 1:1)=0.42.

Example 115-Chloro-N-({(5S)-3-[3-fluoro-4-(piperazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxaniide

[0545]

[0546] is obtained by reacting Example 12 with trifluoroacetic acid inmethylene chloride.

[0547] IC₅₀ value=140 nM;

[0548]¹H-NMR [d₆-DMSO]: 3.01-3.25 (m, 8H), 3.5-3.65 (m, 2H), 3.7-3.9 (m,1H), 4.05-4.2 (m, 1H), 4.75-4.9 (m, 1H), 7.05-7.25 (m, 3H), 7.5 (dd,1H), 7.7 (d, 1H), 8.4 (broad s, 1H), 9.0 (t, 1H).

Example 125-Chloro-N-[((5S)-3-(2,4-bipyridinyl-5-yl)-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0549]

[0550] is obtained analogously from(5S)-5-aminomethyl-3-(2,4-bipyridinyl-5-yl)-2-oxo-1,3-oxazolidin-2-one(preparation see EP-A-789 026).

[0551] R_(f) (SiO₂, ethyl acetate/ethanol 1:2)=0.6;

[0552] MS (ESI) 515 (M+H), Cl pattern.

Example 135-Chloro-N-{[(5S)-2-oxo-3-(4-piperidinophenyl)-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

[0553]

[0554] is obtained from 5-(hydroxymethyl)-3-(4-piperidinophenyl)-1,3-oxazolidin-2-one (preparation see DE 2708236) after mesylation,reaction with potassium phthalimide, hydrazinolysis and reaction with5-chlorothiophene-2-carboxylic acid.

[0555] R_(f) (SiO₂, ethyl acetate/toluene 1:1)=0.31;

[0556] m.p. 205° C.

Example 175-Chloro-N-({(5S)-2-oxo-3-[4-(2oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0557]

[0558] Analogously to the known synthesis scheme (see S. J. Brickner etal., J. Med. Chem. 1996, 39, 673), 1-(4-aminophenyl)pyrrolidin-2-one(preparation see Reppe et al., Justus Liebigs Ann. Chem.; 596; 1955;209) gives, after reaction with benzyloxycarbonyl chloride, followed byreaction with R-glycidyl butyrate, mesylation, reaction with potassiumphthalimide, hydrazinolysis in methanol and reaction with5-chlorothiophene-2-carboxylic acid, finally5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thio-phenecarboxamide. The5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)-phenyl]-1,3-oxazolidin-5-ylmethyl)-2-thiophenecarboxamide obtained in this manner has an IC₅₀ valueof 4 nM (test method for the IC₅₀ value according to Example A-1.a.1described above) “determination of the inhibition of factor Xa”).

[0559] M.p.: 229° C.;

[0560] R_(f) value (SiO₂, toluene/ethyl acetate 1:1)=0.05 (startingmaterial:=0.0);

[0561] MS (ESI): 442.0 (21%, M+Na, Cl pattern), 420.0 (72%, M+H, Clpattern), 302.3 (12%), 215(52%), 145 (100%);

[0562]¹H-NMR (d₆-DMSO, 300 MHz): 2.05 (m,2H), 2.45 (m,2H), 3.6 (t,2H),3.77-3.85 (m,3H), 4.15(t,1H), 4.754.85 (m,1H), 7.2 (d,1H), 7.5 (d,2H),7.65 (d,2H), 7.69 (d,1H), 8.96 (t,1H).

[0563] The individual steps of the synthesis of Example 17 describedabove with the respective precursors are as follows:

[0564] At −20° C., 4 g (22.7 mmol) of 1-(4-aminophenyl)pyrrolidin-2-oneand 3.6 ml (28.4 mmol) of N,N-dimethylaniline in 107 ml oftetrahydrofuran are admixed slowly with 4.27 g (25.03 mmol) of benzylchloroformate. The mixture is stirred at −20° C. for 30 minutes and thenallowed to warm to room temperature. 0.5 l of ethyl acetate are added,and the organic phase is washed with 0.5 l of saturated NaCl solution.The organic phase is separated off and dried with MgSO₄, and the solventis evaporated under reduced pressure. The residue is triturated withdiethyl ether and filtered off with suction. This gives 5.2 g (73.8% oftheory) of benzyl 4-(2-oxo-1-pyrrolidinyl)phenylcarbamate as light-beigecrystals of melting point 174° C.

[0565] At −10° C. and under argon, 1.47 g (16.66 mmol) of isoamylalcohol in 200 ml of tetrahydrofuran are admixed dropwise with 7.27 mlof a 2.5 M solution of n-butyllithium (BuLi) in hexane, a further 8 mnlof BuLi solution being required for the added indicatorN-benzylidenebenzylamine to change colour. The mixture is stirred at−10° C. for 10 minutes and cooled to −78° C., and a solution of 4.7 g(15.14mmol) of benzyl 4-(2-oxo-1-pyrrolidinyl)phenylcarbamate is addedslowly. Another 4 ml of n-BuLi solution are then added until the colourof the indicator changes to pink. The mixture is stirred at −78° C. for10 minutes, 2.62 g (18.17 mmol) of R-glycidyl butyrate are added and themixture is stirred at −78° C. for another 30 minutes.

[0566] Overnight, the mixture is allowed to warm to room temperature,200 ml of water are added and the THF fraction is evaporated underreduced pressure. The aqueous residue is extracted with ethyl acetateand the organic phase is dried with MgSO₄ and evaporated under reducedpressure. The residue is triturated with 500 ml of diethyl ether and theprecipitated crystals are filtered off with suction under reducedpressure.

[0567] This gives 3.76 g (90% of theory) of(5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-oneof melting point 148° C., with an R_(f) value (SiO₂, toluene/ethylacetate 1:1) of 0.04 (starting material=0.3).

[0568] At 0° C., 3.6 g (13.03 mmol) of(5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-oneand 2.9 g (28.67 mmol) of triethylamine are initially charged withstirring in 160 ml of dichloromethane. 1.79 g (15.64 mmol) ofmethanesulphonyl chloride are added with stirring, and the mixture isstirred at 0° C. for 1.5 hours and then at room temperature for 3 h.

[0569] The reaction mixture is washed with water and the aqueous phaseis reextracted with methylene chloride. The combined organic extractsare dried with MgSO₄ and concentrated. The residue (1.67 g) is thendissolved in 70 ml of acetonitrile, admixed with 2.62 g (14.16 mmol) ofpotassium phthalimide and stirred in a closed vessel at 180° C. in amicrowave oven for 45 minutes.

[0570] The mixture is filtered off from insoluble residues, the filtrateis evaporated under reduced pressure and the residue (1.9 g) isdissolved in methanol and admixed with 0.47 g (9.37 mmol) of hydrazinehydrate. The mixture is boiled for 2 hours, cooled, admixed withsaturated sodium bicarbonate solution and extracted six times with atotal of 2 l of methylene chloride. The combined organic extracts of thecrude(5S)-5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-oneare dried with MgSO₄ and concentrated under reduced pressure.

[0571] The end product,5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide,is prepared by dissolving 0.32 g (1.16 mmol) of the(5S)-5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-oneprepared above, 5-chlorothiophene-2-carboxylic acid (0.19 g; 1.16 mmol)and 1-hydroxy-1H-benzotriazole hydrate (HOBT) (0.23 g, 1.51 mmol) in 7.6ml of DMF. 0.29 g (1.51 mmol) ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI) are added, and 0.3g (0.4 ml; 2.32 mmol, 2 equivalents) of diisopropylethylamine (DIEA) areadded dropwise at room temperature. The mixture is stirred at roomtemperature overnight.

[0572] The mixture is evaporated to dryness under reduced pressure andthe residue is dissolved in 3 ml of DMSO and chromatographed on anRP-MPLC using an acetonitrile/water/0.5% TFA gradient. From theappropriate fractions, the acetonitrile fraction is evaporated and theprecipitated compound is filtered off with suction. This gives 0.19 g(39% of theory) of the target compound.

[0573] The following compounds were prepared in an analogous manner:

Example 185-Chloro-N-({(5S)-2-oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0574] Analogously to Example 17, 4-pyrrolidin-1-yl-aniline (Reppe etal., Justus Liebigs Ann. Chem.; 596; 1955; 151) gives the compound5chloro-N-({(5S)-2-oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.

[0575] IC₅₀=40 nM;

[0576] m.p.: 216° C.;

[0577] R_(f) value (SiO₂, toluene/ethyl acetate 1:1)=0.31 [startingmaterial:=0.0].

Example 195-Chloro-N-({(5S)-2-oxo-3-[4-(diethylamino)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0578] Analogously, N,N-diethylphenyl-1,4-diamine (U.S. Pat. No.2,811,555; 1955) gives the compound5-chloro-N-({(5S)-2-oxo-3-[4-(diethylamino)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.

[0579] IC₅₀=270 nM;

[0580] m.p.: 181° C.;

[0581] R_(f) value (SiO₂, toluene/ethyl acetate 1:1)=0.25 [startingmaterial:=0.0].

Example 365-Chloro-N-({(5S)-3-[2-methyl-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamnide

[0582] starting from 2-methyl4-(4-morpholinyl)aniline (J. E. LuValle etal. J. Am. Chem. Soc. 1948, 70, 2223):

[0583] MS (ESI): m/z (%)=436 ([M+H]⁺, 100), Cl pattem;

[0584] HPLC (method 1): rt (%)=3.77 (98).

[0585] IC₅₀: 1.26 μM

Example 375-Chloro-N-{[(5S)-3-(3-chloro-4-morpholinophenyl)-2-oxo-1,3loxazolidin-5-yl]methyl}-2-thiophenecarboxamide

[0586] starting from 3-chloro4(4-morpholinyl)aniline (H. R. Snyder etal. J. Pharm. Sci. 1977, 66, 1204):

[0587] MS (ESI): m/z (%)=456 ([M+H]⁺, 100), Cl₂ pattern;

[0588] HPLC (method 2): rt (%)=4.31 (100).

[0589] IC₅₀: 33 nM

Example 385-Chloro-N-({(5S)-3-[4-(4-morpholinylsulphonyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0590] starting from 4-(4-morpholinylsulphonyl)aniline (Adams et al. J.Am. Chem. Soc. 1939, 61, 2342):

[0591] MS (ESI): m/z (%)=486 ([M+H]⁺, 100), Cl pattern;

[0592] HPLC (method 3): rt (%)=4.07 (100).

[0593] IC₅₀: 2 μM

Example 395-Chloro-N-({(5S)-3-[4-(1-azetidinylsulphonyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0594] starting from 4-(1-azetidinylsulphonyl)aniline:

[0595] MS (DCI, NH₃): m/z (%)=473 ([M+NH]⁺, 100), Cl pattern;

[0596] HPLC (method 3): rt (%)=4.10 (100).

[0597] IC₅₀: 0.84 μM

Example 405-Chloro-N-[((5S)-3-{4-[(dimethylamino)sulphonyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0598] starting from 4-amino-N,N-dimethylbenzenesulphonamide (I. K.Khanna et al. J. Med. Chem. 1997,40, 1619):

[0599] MS (ESI): m/z (%)=444 ([M+H]⁺, 100), Cl pattern;

[0600] HPLC (method 3): rt (%)=4.22 (100).

[0601] IC₅₀: 90 nM

General Method for the Acylation of5-(aminomethyl)-3-[4-(2-oxo-1-pyrro-lidinyl)phenyl]-1,3-oxazolidin-2-onewith carbonyl chlorides

[0602]

[0603] Under argon and at room temperature, an about 0.1 molar solutionof5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one(from Example 45) (1.0 eq.) and absolute pyridine (about 6 eq.) inabsolute dichloromethane is added dropwise to the appropriate acidchloride (2.5 eq.). The mixture is stirred at room temperature for about4 h, and about 5.5 eq of PS-trisamine (Argonaut Technologies) are thenadded. The suspension is stirred gently for 2 h, diluted withdichloromethane/DMF (3:1) and then filtered (the resin is washed withdichloromethane/DMF) and the filtrate is concentrated. If appropriate,the product that is obtained is purified by preparative RP-HPLC.

[0604] The following compounds were prepared in an analogous manner:

Example 41N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide

[0605] LC-MS (method 6): m/z (%)=386 (M+H, 100);

[0606] LC-MS: rt (%)=3.04 (100).

[0607] IC₅₀: 1.3 μM

[0608] General Method for Preparing Acyl Derivatives Starting From5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-oneand carboxylic acids

[0609] The appropriate carboxylic acid (about 2 eq.) and a mixture ofabsolute dichloromethane/DMF (about 9:1) are added to 2.9 eq. ofresin-bonded carbodiimide (PS-carbodiimide, Argonaut Technologies). Themixture is shaken gently at room temperature for about 15 min,5-(aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one(from Example 45) (1.0 eq.) is then added and the mixture is shakenovernight, after which the resin is filtered off (and washed withdichloromethane), and the filtrate is concentrated. If appropriate, theresulting product is purified by preparative RP-HPLC.

[0610] The following compounds were prepared in an analogous manner:

Example 425-Methyl-N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0611] LC-MS: m/z (%)=400 (M+H, 100);

[0612] LC-MS (method 6): rt (%)=3.23 (100).

[0613] IC₅₀: 0.16 μM

Example 435-Bromo-N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0614] LC-MS: m/z (%)=466 (M+H, 100);

[0615] LC-MS (method 5): rt (%)=3.48 (78).

[0616] IC₅₀: 0.014 μM

Example 445-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-13oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0617]

[0618] a)2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione:

[0619] A suspension of2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et al.Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water(9:1, 140 ml) is refluxed for 14 h (the precipitate dissolves, aftersome time again formation of a precipitate). The precipitate (desiredproduct) is filtered off, washed three times with diethyl ether anddried. The combined mother liquors are concentrated under reducedpressure and, after addition of a second portion of2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (2.84 g, 14.0mmol), suspended in ethanol/water (9:1, 70 ml) and refluxed for 13 h(the precipitate dissolves, after some time again formation of aprecipitate). The precipitate (desired product) is filtered off, washedthree times with diethyl ether and dried. Total yield: 10.14 g, 92% oftheory.

[0620] MS (ESI): m/z (%)=418 ([M+Na]⁺, 84), 396 ([M+H]⁺, 93);

[0621] HPLC (method 3): rt (%)=3.34 (100).

[0622] b)2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione:

[0623] Under argon and at room temperature, N,N′-carbonyldiimidazole(2.94 g, 18.1 mmol) and dimethylaminopyridine (a catalytic amount) areadded to a suspension of the amino alcohol (3.58 g, 9.05 mmol) intetrahydrofuran (90 ml). The reaction suspension is stirred at 60° C.for 12 h (the precipitate dissolves, after some time again formation ofa precipitate), admixed with a second portion ofN,N′-carbonyldiimidazole (2.94 g, 18.1 mmol) and stirred at 60° C. foranother 12 h. The precipitate (desired product) is filtered off, washedwith tetrahydrofuran and dried. The filtrate is concentrated underreduced pressure and further product is purified by flash chromatography(dichloromethane/methanol mixtures). Total yield: 3.32 g, 87% of theory.

[0624] MS (ESI): m/z (%)=422 ([M+H]⁺, 100);

[0625] HPLC (method 4): rt (%)=3.37 (100).

[0626] c)5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide:

[0627] At room temperature, methylamine (40% strength in water, 10.2 ml,0.142 mol) is added dropwise to a suspension of the oxazolidinone (4.45g, 10.6 mmol) in ethanol (102 ml). The reaction mixture is refluxed for1 h and concentrated under reduced pressure. The crude product is usedwithout further purification for the next reaction.

[0628] Under argon and at 0° C., 5-chlorothiophene-2-carbonyl chloride(2.29 g, 12.7 mmol) is added dropwise to a solution of the amine inpyridine (90 ml). Ice-cooling is removed and the reaction mixture isstirred at room temperature for 1 h and admixed with water.Dichloromethane is added and the phases are separated, and the aqueousphase is then extracted with dichloromethane. The combined organicphases are dried (sodium sulphate), filtered and concentrated underreduced pressure. The desired product is purified by flashchromatography (dichloromethane/methanol mixtures).

[0629] Total yield: 3.92 g, 86% of theory.

[0630] M.p: 232-233° C.;

[0631]¹H NMR (DMSO-d⁶, 200 MHz): 9.05-8.90 (t, J=5.8 Hz, 1H), 7.70 (d,J=4.1 Hz, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.41 (d, J=9.0 Hz, 2H), 7.20 (d,J=4.1 Hz, 1H), 4.93-4.75 (m, 1H), 4.27-4.12 (m, 3H), 4.02-3.91 (m, 2H),3.91-3.79 (dd, J=6.1 Hz, 9.2 Hz, 1H), 3.76-3.66 (m, 2H), 3.66-3.54 (m,2H);

[0632] MS (ESI): m/z (%)=436 ([M+H]⁺, 100, Cl pattern);

[0633] HPLC (method 2): rt (%)=3.60 (100);

[0634] [α]²¹ _(D)=−38° (c 0.2985, DMSO); ee: 99%.

[0635] IC₅₀: 0.7 nM

[0636] The following compounds were prepared in an analogous manner:

Example 455-Methyl-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0637] MS (ESI): m/z (%)=831 ([2M+H]⁺, 100), 416 ([M+H]⁺, 66);

[0638] HPLC (method 3): rt (%)=3.65 (100).

[0639] IC₅₀: 4.2 nM

Example 465-Bromo-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0640] MS (ESI): m/z (%)=480 ([M+H]⁺, 100, Br pattern);

[0641] HPLC (method 3): rt (%)=3.87 (100).

[0642] IC₅₀: 0.3 nM

Example 475-Chloro-N-{[(5S)-3-(3-isopropyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

[0643]

[0644] 200 mg (0.61 mmol) of6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-isopropyl-1,3-benzoxazol-2(3H)-onehydrochloride (EP 738726) are suspended in 5 ml of tetrahydrofuran andadmixed with 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol)of 5-chlorothiophene-2-carbonyl chloride. The reaction mixture isstirred at room temperature overnight and then concentrated. The productis isolated by column chromatography (silica gel, methylenechloride/ethanol=50/1 to 20/1). This gives 115 mg (43% of theory) of thedesired compound.

[0645] MS (ESI): m/z (%)=436 (M+H, 100);

[0646] HPLC (method 4): rt=3.78 min.

[0647] The following compounds were prepared in an analogous manner;Example No. Structure M.p. [° C.] IC₅₀ [μM] 48

210 0.12 49

234 0.074 50

195 1.15 51

212 1.19 52

160 0.19 53

MS (ESI): m/z (%) =431 ([M + H]⁺, 100), Cl pattern 0.74 54

221 0.13 from 5-amino-2-pyrrolidino-benzonitril (Grell, W., Hurnaus, R.,Griss, G., Sauter, R.; Rupprecht, E. et al.; J. Med. Chem. 1998, 41;5219) 55

256 0.04 from 3-(4-amino-phenyl)-oxazolidin-2-one (Artico, M. et al.;Farmaco Ed. Sci. 1969, 24; 179) 56

218 0.004 57

226 0.58 255

228-230

[0648] Examples 20 to 30 and 58 to 139 below refer to process variant[B], and Examples 20 and 21 describe the preparation of precursors.

Example 20 Preparation of N-allyl-5-chloro-2-thiophenecarboxamide

[0649]

[0650] An ice-cooled solution of 2.63 ml (35 mmol) of allylamine in 14.2ml of absolute pyridine and 14.2 ml of absolute THF is admixed dropwisewith 5-chloro-thiophene-2-carbonyl chloride (7.61 g, 42 mmol).Ice-cooling is removed and the mixture is stirred at room temperaturefor 3 h and then concentrated under reduced pressure. The residue isadmixed with water and the solid is filtered off. The crude product ispurified by flash chromatography over silica gel (dichloromethane).

[0651] Yield: 7.20 g (99% of theory);

[0652] MS (DCI, NH₄): m/z (%)=219 (M+NH₄, 100), 202 (M+H, 32);

[0653] HPLC (method 1): rt (%)=3.96 min (98.9).

Example 21 Preparation of5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide

[0654]

[0655] An ice-cooled solution of 2.0 g (9.92 mmol) ofN-allyl-5-chloro-2-thiophenecarboxamide in 10 ml of dichloromethane isadmixed with meta-chloroperbenzoic acid (3.83 g, about 60% strength).The mixture is stirred overnight, during which it is allowed to warm toroom temperature, and is then washed with 10% sodium hydrogen sulphatesolution (three times). The organic phase is washed with saturatedsodium bicarbonate solution (twice) and with saturated sodium chloridesolution, dried over magnesium sulphate and concentrated. The product ispurified by silica gel chromatography (cyclohexane/ethyl acetate 1:1).

[0656] Yield: 837 mg (39% of theory);

[0657] MS (DCI, NH₄): m/z (%)=253 (M+NH₄, 100), 218 (M+H, 80);

[0658] HPLC (method 1): rt (%)=3.69 min (about 80).

General Method for Preparing SubstitutedN-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamnide DerivativesStarting From 5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide

[0659]

[0660] At room temperature or at temperatures up to 80° C.,5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide (1.0 eq.) is addeda little at a time to a solution of the primary amine or anilinederivative (1.5 to 2.5 eq.) in 1,4-dioxane, 1,4-dioxane/water mixturesor ethanol, ethanol/water mixtures (about 0.3 to 1.0 mol/l). The mixtureis stirred for 2 to 6 hours and then concentrated. From the reactionmixture, the product can be isolated by silica gel chromatography(cyclohexane/ethyl acetate mixtures, dichloromethane/methanol mixturesor dichloromethane/methanol/triethylamine mixtures).

[0661] The following compounds were prepared in an analogous manner:

Example 22N-[3-(Benzylamino)-2-hydroxypropyl]-5-chloro-2-thiophenecarboxamide

[0662] MS (ESI): m/z (%)=325 (M+H, 100);

[0663] HPLC (method 1): rt (%)=3.87 min (97.9).

Example 235-Chloro-N-[3-(3-cyanoanilino)-2-hydroxypropyl]-2thiophenecarboxamide

[0664] MS (ESI): m/z (%)=336 (M+H, 100);

[0665] HPLC (method 2): rt (%)=4.04 min (100).

Example 245-Chloro-N-[3-(4-cyanoanilino)-2-hydroxypropyl]-2-thiophenecarboxarnide

[0666] MS (ESI): m/z (%)=336 (M+H, 100);

[0667] HPLC (method 1): rt (%)=4.12 min (100).

Example 255-Chloro-N-{3-[4-(cyanomethyl)anilino]-2-hydroxypropyl}-2-thiophenecarboxamnide

[0668] MS (ESI): m/z (%)=350 (M+H, 100);

[0669] HPLC (method 4): rt (%)=3.60 min (95.4).

Example 265-Chloro-N-{3-[3-(cyanomethyl)anilino]-2-hydroxypropyl}-2-thiophenecarboxamide

[0670] MS (ESI): m/z (%)=350 (M+H, 100);

[0671] HPLC (method 4): rt(%)=3.76 min (94.2).

Example 58 tert-Butyl4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]-benzylcarbamate

[0672] starting from tert-butyl 4-aminobenzylcarbamate (Bioorg. Med.Chem. Lett.; 1997; 1921-1926):

[0673] MS (ES-pos): m/z (%)=440 (M+H, 100), (ES-neg): m/z (%)=438 (M−H,100);

[0674] HPLC (method 1): rt (%)=4.08 (100).

Example 59 tert-Butyl4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]-phenyl-carbamate

[0675] starting from N-tert-butyloxycarbonyl-1,4-phenylenediamine:

[0676] MS (ESI): m/z (%)=426 (M+H, 45), 370 (100);

[0677] HPLC (method 1): rt (%)=4.06 (100).

Example 60 tert-Butyl2-hydroxy-3-{[4-(2-oxo-1-pyrrolidinyl)phenyl]amino}propyl-carbamate

[0678] starting from 1-(4-aminophenyl)-2-pyrrolidinone (Justus LiebigsAnn. Chem.; 1955; 596; 204):

[0679] MS (DCI, NH₃): m/z (%)=350 (M+H, 100);

[0680] HPLC (method 1): rt (%)=3.57 (97).

Example 615-Chloro-N-(3-{[3-fluoro-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-2-thiophenecarboxamide

[0681] 800 mg (3.8 mmol) of 4-(4-amino-2-fluorophenyl)-3-morpholinoneand 700 mg (3.22 mmol) of5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide in 15 ml of ethanoland 1 ml of water are heated under reflux for 6 hours. The mixture isconcentrated under reduced pressure and treated with ethyl acetate,precipitated crystals are filtered off with suction and the motherliquor is chromatographed giving 276 mg (17% of theory) of the targetcompound.

[0682] R_(f) (ethyl acetate): 0.25.

Example 62(N-(3-Anilino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide startingfrom aniline:

[0683] MS (DCI, NH₃): m/z (%)=311 ([M+H]⁺, 100), Cl pattern;

[0684] HPLC (method 3): rt (%)=3.79 (100).

Example 635-Chloro-N-(2-bydroxy-3-{[4-(3-oxo-4morpholinyl)phenyl]amino}propyl)-2-thiophenecarboxarnide

[0685] starting from 4-(4-aminophenyl)-3-morpholinone:

[0686] MS (ESI): m/z (%)=410 ([M+H]⁺, 50), Cl pattern;

[0687] HPLC (method 3): rt (%)=3.58 (100).

Example 64N-[3-({4-[Acetyl(cyclopropyl)amino]phenyl}amino)-2-hydroxypropyl]-5-chloro-2-thiophenecarboxamide

[0688] starting from N-(4-aminophenyl)-N-cyclopropylacetamide:

[0689] MS (ESI): m/z (%)=408 ([M+H]⁺, 100), Cl pattern;

[0690] HPLC (method 3): rt (%)=3.77 (100).

Example 65N-[3-({4-[Acetyl(methyl)amino]phenyl}amino)-2-hydroxypropyl]-5-chloro-2-thiophenecarboxamide

[0691] starting from N-(4-aminophenyl)-N-methylacetamide:

[0692] MS (ESI): m/z (%)=382 (M+H, 100);

[0693] HPLC (method 4): rt=3.31 min.

Example 665-Chloro-N-(2-hydroxy-3-{[4-(1H-1,2,3-triazol-1-yl)phenyl]amino}propyl)-2-thiophenecarboxamide

[0694] starting from 4-(1H-1,2,3-triazol-1-yl)aniline (Bouchet et al.;J. Chem. Soc. Perkin Trans.2; 1974; 449):

[0695] MS (ESI): m/z (%)=378 (M+H, 100);

[0696] HPLC (method 4): rt=3.55 min.

Example 67 tert-butyl1-{4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-aminolphenyl}-L-prolinate

[0697] MS (ESI): m/z (%)=480 (M+H, 100);

[0698] HPLC (method 4): rt=3.40 min.

Example 681-{4-[(3-{[(5-Chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]phenyl}-4-piperidinecarboxamide

[0699] MS (ESI): m/z (%)=437 (M+H, 100);

[0700] HPLC (method 4): rt=2.39 min.

Example 691-{4-[(3-{[(5-Chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-amino]phenyl}-3-piperidinecarboxamide

[0701] MS (ESI): mlz (%)=437 (M+H, 100);

[0702] HPLC (method 4): rt=2.43 min.

Example 70 5-Chloro-N-(2-hydroxy-3-{[4-(4-oxo-1-piperidinyl)phenyl]amino}propyl)-2-thiophenecarboxamide

[0703] MS (ESI): m/z (%)=408 (M+H, 100);

[0704] HPLC (method 4): rt=2.43 min.

Example 711-{4-[(3-{[(5-Chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)amino]phenyl)-L-prolinamide

[0705] MS (ESI): m/z (%)=423 (M+H, 100);

[0706] HPLC (method 4): rt=2.51 min.

Example 725-Chloro-N-[2-hydroxy-3-({4-[3-(hydroxymethyl)-1-piperidinyl]phenyl}-amino)propyl]-2-thiophenecarboxamide

[0707] MS (ESI): m/z (%)=424 (M+H, 100);

[0708] HPLC (method 4): rt=2.43 min.

Example 735-Chloro-N-[2-hydroxy-3-({4-[2-(hydroxymethyl)-1-piperidinyl]phenyl}-amino)propyl]-2-thiophenecarboxamide

[0709] MS (ESI): m/z (%)=424 (M+H, 100);

[0710] HPLC (method 4): rt=2.49 min.

Example 74 Ethyl1-{4-[(3-{[(5-chloro-2-thienyl)carbonyl]amino}-2-hydroxypropyl)-amino]phenyl}-2-piperidinecarboxylate

[0711] MS (ESI): m/z (%)=466 (M+H, 100);

[0712] HPLC (method 4): rt=3.02 min.

Example 755-Chloro-N-[2-hydroxy-3-({4-[2-(hydroxymethyl)-1-pyrrolidinyl]phenyl}amino)-propyl]-2-thiophenecarboxamide

[0713] MS (ESI): m/z (%)=410 (M+H, 100);

[0714] HPLC (method 4): rt=2.48 min.

Example 765-Chloro-N-(2-hydroxy-3-{[4-(2-methylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl)phenyl]amino}propyl)-2-thiophenecarboxaride

[0715] MS (ESI): m/z (%)=437 (M+H, 100).

[0716] HPLC (method 5): rt=1.74 min.

Example 775-Chloro-N-(2-hydroxy-3-{[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]-amino}propyl)-2-thiophenecarboxamide

[0717] MS (ESI): m/z (%)=448 (M+H, 100);

[0718] HPLC (method 4): rt=3.30 min.

Example 785-Chloro-N-(2-hydroxy-3-{[4-(2-oxo-1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]-amino}propyl)-2-thiophenecarboxamide

[0719] MS (ESI): m/z (%)=462 (M+H, 100);

[0720] HPLC (method 4): rt=3.50 min.

Example 795-Chloro-N-(3-{[3-chloro-4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxy-propyl)-2-thiophenecarboxamide

[0721] MS (ESI): m/z (%)=444 (M+H, 100);

[0722] HPLC (method 4): rt=3.26 min.

Example 805-Chloro-N-(2-hydroxy-3-{4-(3-oxo-4-morpholinyl)-3-(trifluoromethyl)phenyl]-amino}propyl)-2-thiophenecarboxamide

[0723] MS (ESI): m/z (%)=478 (M+H, 100);

[0724] HPLC (method 4): rt=3.37 min.

Example 815-Chloro-N-(2-hydroxy-3-{[3-methyl-4-(3-oxo-4-morpholinyl)phenyl]amino}-propyl)-2-thiophenecarboxanide

[0725] MS (ESI): m/z (%)=424 (M+H, 100);

[0726] HPLC (method 4): rt=2.86 min.

Example 825-Chloro-N-(3-{[3-cyano4-(3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-2-thiophenecarboxamide

[0727] MS (ESI): m/z (%)=435 (M+H, 100);

[0728] HPLC (method 4): rt=3.10 min.

Example 835-Chloro-N-(3-{[3-chloro-4-(1-pyrrolidinyl)phenyl]amino}-2-hydroxypropyl)-2-thiophenecarboxamide

[0729] MS (ESI): m/z (%)=414 (M+H, 100);

[0730] HPLC (method 4): rt=2.49 min.

Example 845-Chloro-N-(3-{[3-chloro-4-(2-oxo-1-pyrrolidinyl)phenyl]amino}-2-hydroxypropyl)-2-thiophenecarboxamide

[0731] MS (ESI): m/z (%)=428 (M+H, 100);

[0732] HPLC (method 4): rt=3.39 min.

Example 855-Chloro-N-(3-{[3,5-dimethyl-4-(3-oxo-4-morpholinyl)phenyl]amino)-2-hydroxypropyl)-2-thiophenecarboxamide

[0733] MS (ESI): m/z (%)=438 (M+H, 100);

[0734] HPLC (method 4): rt=2.84 min.

Example 86N-(3-{[3-(Aminocarbonyl)-4-(4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide

[0735] MS (ESI): m/z (%)=439 (M+H, 100);

[0736] HPLC (method 4): rt=2.32 min.

Example 875-Chloro-N-(2-hydroxy-3-{[3-methoxy-4-(4-morpholinyl)phenyl]amino}propyl)-2-thiophenecarboxamide

[0737] MS (ESI): m/z (%)=426 (M+H, 100);

[0738] HPLC (method 4): rt=2.32 min.

Example 88N-(3-[3-Acetyl-4-(4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide

[0739] MS (EST): m/z (%)=438 (M+H, 100);

[0740] HPLC (method 4): rt=2.46 min.

Example 89N-(3-{[3-Amino-4-(3-oxo4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide

[0741] MS (ESI): m/z (%)=425 (M+H, 100);

[0742] HPLC (method 4): rt=2.45 min.

Example 905-Chloro-N-(3-{[3-chloro-4-(2-methyl-3-oxo-4-morpholinyl)phenyl]amino}-2-hydroxypropyl)-2-thiophenecarboxaniide

[0743] MS (ESI): m/z (%)=458 (M+H, 100);

[0744] HPLC (method 4): rt=3.44 min.

Example 915-Chloro-N-(3-{[3-chloro-4-(2-methyl-5-oxo-4-morpholinyl)phenyl]amino)-2-hydroxypropyl)-2-thiophenecarboxamide

[0745] MS (ESI): m/z (%)=458 (M+H, 100);

[0746] HPLC (method 4): rt=3.48 min.

Example 91a5-Chloro-N-[2-hydroxy-3-(14-[(3oxo4morpholinyl)methyl]phenyl}amino)-propyl]-2-thiophenecarboxamide

[0747] starting from 4-(4-amino-benzyl)-3-morpholinone (Surrey et al.;J. Amer. Chem. Soc.; 77; 1955; 633):

[0748] MS (ESI): m/z (%)=424 (M+H, 100);

[0749] HPLC (method 4): rt=2.66 min.

General Method for Preparing 3-substituted5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamidederivatives starting from substitutedN-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide derivatives

[0750]

[0751] At room temperature, carbodiimidazole (1.2 to 1.8 eq.) or asimilar phosgene equivalent are added to a solution of the substitutedN-(3-amino-2-hydroxypropyl)-5-chloro-2-thiophenecarboxamide derivative(1.0 eq.) in absolute THF (about 0.1 mol/1). At room temperature or, ifappropriate, at elevated temperature (up to 70° C.), the mixture isstirred for 2 to 18 h and then concentrated under reduced pressure. Theproduct can be purified by silica gel chromatography(dichloromethane/methanol mixtures or cyclohexane/ethyl acetatemixtures).

[0752] The following compounds were prepared in an analogous manner:

Example 27N-[(3-Benzyl-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide

[0753] MS (DCI, NH₄): m/z (%)=372 (M+Na, 100), 351 (M+H, 45);

[0754] HPLC (method 1): rt (%)=4.33 min (100).

Example 285-Chloro-N-{[3-(3-cyanophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

[0755] MS (DCI, Ne): m/z (%)=362 (M+H, 42), 145 (100);

[0756] HPLC (method 2): rt (%)=4.13 min (100).

Example 295-Chloro-N-({3-[4-(cyanomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0757] MS (ESI): m/z (%)=376 (M+H, 100);

[0758] HPLC (method 4): rt=4.12 min

Example 305-Chloro-N-({3-[3-(cyanomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0759] MS (ESI): m/z (%)=376 (M+H, 100);

[0760] HPLC (method 4): rt=4.17 min

Example 92 tert-Butyl4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]benzylcarbamate

[0761] starting from Example 58:

[0762] MS (ESI): m/z (%)=488 (M+Na, 23), 349 (100);

[0763] HPLC (method 1): rt (%)=4.51 (98.5).

Example 93 tert-Butyl4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenylcarbamate

[0764] starting from Example 59:

[0765] (ESI): m/z (%)=493 (M+Na, 70), 452 (M+H, 10), 395 (100);

[0766] HPLC (method 1): rt (%)=4.41 (100).

Example 94 tert-Butyl2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl-carbamate

[0767] starting from Example 60:

[0768] MS (DCI, NH₃): m/z (%)=393 (M+NH₄, 100);

[0769] HPLC (method 3): rt (%)=3.97 (100).

Example 955-Chloro-N-({3-[3-fuoro-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxanide

[0770]

[0771] 260 mg (0.608 mmol) of5-chloro-N-(3-{[3-fluoro4-(3-oxo4-morpholinyl)phenyl]-amino}-2-hydroxypropyl)-2-thiophenecarboxamide(from Examnple 61), 197 mg (1.22 mmol) of carbonylimidazole and 7 mg ofdimethylaminopyridine in 20 ml of dioxane are boiled under reflux for 5hours. 20 ml of acetonitrile are then added, and the mixture is stirredin a closed vessel in a microwave oven at 180° C. for 30 minutes. Thesolution is concentrated using a rotary evaporator and chromatographedon an RP-HPLC column. This gives 53 mg (19% of theory) of the targetcompound.

[0772] NMR (300 MHz, d₆-DMSO): δ=3.6-3.7 (m,4H), 3.85 (dd,1H), 3.95(m,2H), 4.2 (m,1H), 4.21 (s,2H), 4.85 (m,1H), 4.18 (s,2H), 7.19(d,1H,thiophene), 7.35 (dd,1H), 7.45 (t,1H), 7.55 (dd,1H), 7.67(d,1H,thiophene), 8.95 (t,1H,CONH).

Example 965-Chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0773] starting from Example 62:

[0774] MS (ESI): m/z (%)=359 ([M+Na]⁺, 71), 337 ([M+H]⁺, 100), Clpattern;

[0775] HPLC (method 3): rt (%)=4.39 (100).

[0776] IC₅₀: 2 μM

Example 975-Chloro-N-(12-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

[0777] starting from Example 63:

[0778] MS (ESI): m/z (%)=458 ([M+Na]⁺, 66), 436 ([M+H]⁺, 100), Clpattern;

[0779] HPLC (method 3): rt (%)=3.89 (100).

[0780] IC₅₀: 1.4 nM

Example 98N-[(3-{4-[Acetyl(cyclopropyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide

[0781] starting from Example 64:

[0782] MS (ESI): m/z (%)=456 ([M+Na]⁺, 55), 434 ([M+H]+, 100), Clpattern;

[0783] HPLC (method 3): rt (%)=4.05 (100).

[0784] IC₅₀: 50 nM

Example 99N-[(3-{4-[Acetyl(methyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxaniide

[0785] MS (ESI): m/z (%)=408 (M+H, 30), 449 (M+H+MeCN, 100);

[0786] HPLC (method 4): rt=3.66 min.

Example 1005-Chloro-N-({2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

[0787] MS (ESI): m/z (%)=404 (M+H, 45), 445 (M+H+MeCN, 100);

[0788] HPLC (method 4): rt=3.77 min.

Example 101 Tert-butyl1-{4-[5-({[(5-chloro-2thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-L-prolinate

[0789] MS (ESI): m/z (%)=450 (M+H−56, 25), 506 (M+H, 100);

[0790] HPLC (method 4): rt=5.13 min.

Example 1021-{4-[5-(([(5-Chloro-2-thienyl)carbonyl]aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-4-piperidinecarboxamide

[0791] MS (ESI): m/z (%)=463 (M+H, 100);

[0792] HPLC (method 4): rt=2.51 min.

Example 1031-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-3-piperidinecarboxamide

[0793] MS (ESI): m/z (%)=463 (M+H, 100);

[0794] HPLC (method 4): rt=2.67 min.

Example 1045-Chloro-N-({2-oxo-3-[4-(4-oxo-1-piperidinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0795] MS (ESI): m/z (%)=434 (M+H, 40), 452 (M+H+H₂O, 100), 475(M+H+MeCN, 60);

[0796] HPLC (method 4): rt=3.44 min.

Example 1051-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-L-prolinamide

[0797] MS (ESI): m/z (%)=449 (M+H, 100);

[0798] HPLC (method 4): rt=3.54 min.

Example 1065-Chloro-N-[(3-{4-[3-(hydroxymethyl)-1-piperidinyl]phenyl}-2-oxol,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0799] MS (ESI): m/z (%)=450 (M+H, 100);

[0800] HPLC (method 5): rt=2.53 min.

Example 1075-Chloro-N-[(3-{4-[2-(hydroxymethyl)-1-piperidinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0801] MS (ESI): m/z (%)=450 (M+H, 100);

[0802] HPLC (method 5): rt=2.32 min.

Example 108 Ethyl1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-piperidinecarboxylate

[0803] MS (ESI): m/z (%)=492 (M+H, 100);

[0804] HPLC (method 5): rt=4.35 min.

Example 1095-Chloro-N-[(3-{4-[2-(hydroxymethyl)-1-pyrrolidinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxarnide

[0805] MS (ESI): m/z (%)=436 (M+H, 100);

[0806] HPLC (method 4): rt=2.98 min.

Example 1105-Chloro-N-({2-oxo-3-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0807] MS (ESI): m/z (%)=474 (M+H, 100);

[0808] HPLC (method 4): rt=4.63 min.

Example 1115-Chloro-N-({3-[4-(2-methylhexahydro-5H-pyrrolo[3,4d]isoxazol-5-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0809] MS (ESI): m/z (%)=463 (M+H, 100);

[0810] HPLC (method 4): rt=2.56 min.

Example 1125-Chloro-N-({2-oxo-3-[4-(2-oxo-1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0811] MS (ESI): m/z (%)=488 (M+H, 100);

[0812] HPLC (method 4): rt=3.64 min.

Example 1135-Chloro-N-({3-[3-chloro4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0813] MS (ESI): m/z (%)=470 (M+H, 100);

[0814] HPLC (method 4): rt=3.41 min.

Example 1145-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)-3-(trifluoromethyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0815] MS (ESI): m/z (%)=504 (M+H, 100);

[0816] HPLC (method 4): rt=3.55 min.

Example 1155-Chloro-N-({3-[3-methyl-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0817] MS (ESI): m/z (%)=450 (M+H, 100);

[0818] HPLC (method 4): rt=3.23 min.

Example 1165-Chloro-N-({3-[3-cyano-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0819] MS (ESI): m/z (%)=461 (M+H, 100);

[0820] HPLC (method 4): rt=3.27 min.

Example 1175-Chloro-N-({3-[3-chloro-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0821] MS (ESI): m/z (%)=440 (M+H, 100);

[0822] HPLC (method 4): rt=3.72 min.

Example 1185-Chloro-N-({3-[3-chloro-4-(2-oxo-1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamnide

[0823] MS (ESI): m/z (%)=454 (M+H, 100);

[0824] HPLC (method 4): rt=3.49 min.

Example 1195-Chloro-N-({3-[3,5-dimethyl-4-(3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0825] MS (ESI): m/z (%)=464 (M+H, 100);

[0826] HPLC (method 4): rt=3.39 min.

Example 120N-({3-[3-(Aminocarbonyl)-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

[0827] MS (ESI): m/z (%)=465 (M+H, 100);

[0828] HPLC (method 4): rt=3.07 min.

Example 1215-Chloro-N-({3-[3-methoxy-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0829] MS (ESI): m/z (%)=452 (M+H, 100);

[0830] HPLC (method 4): rt=2.86 min.

Example 122N-({3-[3-Acetyl-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

[0831] MS (ESI): m/z (%)=464 (M+H, 100);

[0832] HPLC (method 4): rt=3.52 min.

Example 123N-({3-[3-Amino-4-(3-oxo4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophenecarboxamide

[0833] MS (ESI): m/z (%)=451 (M+H, 100);

[0834] HPLC (method 6): rt=3.16 min.

Example 1245-Chloro-N-({3-[3-chloro-4-(2-methyl-3-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0835] MS (ESI): m/z (%)=484 (M+H, 100);

[0836] HPLC (method 4): rt=3.59 min.

Example 1255-Chloro-N-({3-[3-chloro-4-(2-methyl-5-oxo-4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0837] MS (ESI): m/z (%)=484 (M+H, 100);

[0838] HPLC (method 4): rt=3.63 min.

Example 125a5-ChloroN-[(2-oxo-3-{4-[(3-oxo-4-morpholinyl)methyl]phenyl)-1,3-oxazolidin5-yl)methyl]-2-thiophenecarboxamide

[0839] MS (ESI): m/z (%)=450 (M+H, 100);

[0840] HPLC (method 4): rt=3.25 min.

[0841] Via epoxide opening with an amine and subsequent cyclization togive the corresponding oxazolidinone, it was also possible to preparethe following compounds: Example No. Structure M.p. [° C.] IC₅₀ [μM] 126

229Z 0.013 127

159 0.0007

198 0.002 129

196 0.001 130

206 0.0033 130a

194 131

195 0.85 132

206 0.12 133

217 0.062 134

207 0.48 from 1-(4-amino-phenyl)-piperidin-3-ol (Tong, L. K. J. et al,;J. Amer. Chem. Soc. 1960; 82, 1988). 135

202 1.1 136

239 1.2 137

219 0.044 138

 95 0.42 139

217 1.7

[0842] Examples 14 to 16 below are working examples for the optionaloxidation step.

Example 145-Chloro-N-({(5S)-3-[3-fuoro-4-(1-oxo-1[lambda]⁴,4-thiazinan4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0843]

[0844] At 0° C., 5-chloro-N-(((5S)-3-[3-fluoro4-(1,4-thiazinan4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide(0.1 g, 0.22 mmol) from Example 3 in methanol (0.77 ml) is added to asolution of sodium periodate (0.05 g, 0.23 mmol) in water (0.54 ml), andthe mixture is stirred at 0° C. for 3 h. 1 ml of DMF is then added, andthe mixture is stirred at RT for 8 h. After addition of a further 50 mgof sodium periodate, the mixture is once more stirred at RT overnight.The mixture is then admixed with 50 ml of water, and the insolubleproduct is filtered off with suction. Washing with water and dryinggives 60 mg (58% of theory) of crystals.

[0845] M.p.: 257° C.;

[0846] R_(f) (silica gel, toluene/ethyl acetate 1:1)=0.54 (startingmaterial=0.46);

[0847] IC₅₀ value=1.1 μM;

[0848] MS (DCI) 489 (M+NH₄), Cl pattern.

Example 15 Preparation of5-chloro-N-({(5S)-3-[4-(1,1-dioxo-1[lambda]⁶,4-thiazinan-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0849]

[0850]5-Chloro-N-({(5S)-3-[3-fluoro4-(1,4-thiazinan4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide from Example 3 (0.1 g, 0.22 mmol) in3.32 ml of a mixture of 1 part of water and 3 parts of acetone isadmixed with 80 mg (0.66 mmol) of N-methylmorpholine N-oxide (NMO) and0.1 ml of a 2.5% strength solution of osmium tetroxide in2-methyl-2-propanol. The mixture is stirred at room temperatureovernight, and another 40 mg of NMO are added. The mixture is stirredfor a further night and then poured into 50 ml of water and extractedthree times with ethyl acetate. The organic phase gives, after dryingand concentrating, 23 mg and the aqueous phase, after removal of theinsoluble solid by filtration with suction, 19 mg (in total 39% oftheory) of the target compound.

[0851] M.p.: 238° C.;

[0852] R_(f) (toluene/ethyl acetate 1:1)=0.14 (starting material=0.46);

[0853] IC₅₀ value=210 nM;

[0854] MS (DCI): 505 (M+NH₄), Cl pattern.

Example 165-Chloro-N-{[(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamideN-oxide

[0855] is obtained by treating5-chloro-N-{[(5S)-3-(3-fluoro4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamidefrom Example 1 with the magnesium salt of monoperoxyphthalic acid.

[0856] MS (ESI): 456 (M+H, 21%, Cl pattern), 439 (100%).

[0857] The Examples 31 to 35 and 140 to 147 below refer to the optionalamidination step.

[0858] General Method for Preparing Amidines and Amidine DerivativesStarting From cyanomethylphenyl-substituted5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamidederivatives

[0859] The cyanomethylphenyl-substituted5-chloro-N-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamidederivative in question (1.0 eq.) is, together with triethylamine (8.0eq.), stirred at RT in a saturated solution of hydrogen sulphide inpyridine (about 0.05-0.1 mol/l) for one to two days. The reactionmixture is diluted with ethyl acetate (EtOAc) and washed with 2 Nhydrochloric acid. The organic phase is dried with MgSO₄, filtered andconcentrated under reduced pressure.

[0860] The crude product is dissolved in acetone (0.01-0.1 mol/l) andadmixed with methyl iodide (40 eq.). The reaction mixture is stirred atroom temperature (RT) for 2 to 5 h and then concentrated under reducedpressure.

[0861] The residue is dissolved in methanol (0.01-0.1 mol/l) and, toprepare the unsubstituted amidines, admixed with ammonium acetate (3eq.) and ammonium chloride (2 eq.). To prepare the substituted amidinederivatives, primary or secondary amines (1.5 eq.) and acetic acid (2eq.) are added to the methanolic solution. After 5-30 h, the solvent isremoved under reduced pressure and the residue is purified bychromatography over an RP8 silica gel column (water/acetonitrile9/1-1/1+0.1% trifluoroacetic acid).

[0862] The following compounds were prepared in an analogous manner:

Example 31N-({3-[4-(2-Amino-2-iminoethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

[0863] MS (ESI): m/z (%)=393 (M+H, 100);

[0864] HPLC (method 4): rt=2.63 min

Example 325-Chloro-N-({3-[3-(4,5dihydro-1H-imidazol-2-ylmethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0865] MS (ESI): m/z (%)=419 (M+H, 100);

[0866] HPLC (method 4): rt=2.61 min

Example 335-Chloro-N-[(3-{3-[2-imino-2-(4-morpholinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0867] MS (ESI): m/z (%)=463 (M+H, 100);

[0868] HPLC (method 4): rt=2.70 min

Example 345-Chloro-N-[(3-{3-[2-imino-2-(1-pyrrolidinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0869] MS (ESI): m/z (%)=447 (M+H, 100);

[0870] HPLC (method 4): rt=2.82 min

Example 35N-({3-[3-(2-Amino-2-iminoethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

[0871] MS (ESI): m/z (%)=393 (M+H, 100);

[0872] HPLC (method 4): rt=2.60 min

Example 1405-Chloro-N-({3-[4-(4,5-dihydro-1H-imidazol-2-ylmethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0873] MS (ESI): m/z (%)=419 (M+H, 100);

[0874] HPLC (method 4): rt=2.65 min

Example 1415-Chloro-N-[(3-{4-[2-imino-2-(4-morpholinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0875] MS (ESI): m/z (%)=463 (M+H, 100);

[0876] HPLC (method 4): rt=2.65 min

Example 1425-Chloro-N-[(3-{4-[2-imino-2-(1-piperidinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0877] MS (ESI): m/z (%)=461 (M+H, 100);

[0878] HPLC (method 4): rt=2.83 min

Example 1435-Chloro-N-[(3-{4-[2-imino-2-(1-pyrrolidinyl)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0879] MS (ESI): m/z (%)=447 (M+H, 100);

[0880] HPLC (method 4): rt=2.76 min

Example 1445-Chloro-N-[(3-{4-[2-(cyclopentylamino)-2-iminoethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0881] MS (ESI): m/z (%)=461 (M+H, 100);

[0882] HPLC (method 4): rt=2.89 mmn

Example 1455-Chloro-N-{[3-(4-{2-imino-2-[(2,2,2-trifluoroethyl)amino]ethyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

[0883] MS (ESI): m/z (%)=475 (M+H, 100);

[0884] HPLC (method 4): rt=2.79 min

Example 146N-({3-[4-(2-Anilino-2-iminoethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

[0885] MS (ESI): m/z (%)=469 (M+H, 100);

[0886] HPLC (method 4): rt=2.83 min

Example 1475-Chloro-N-[(3-{4-[2-imino-2-(2-pyridinylamino)ethyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0887] MS (ESI): m/z (%)=470 (M+H, 100);

[0888] HPLC (method 4): rt=2.84 min

[0889] Examples 148 to 151 below refer to the removal of BOC aminoprotective groups:

[0890] General Method for Removing Boc Protective Groups(tert-butyloxycarbonyl)

[0891] Aqueous trifluoroacetic acid (TFA, about 90%) is added dropwiseto an ice-cooled solution of a tert-butyloxycarbonyl-(Boc) protectedcompound in chloroform or dichloromethane (about 0.1 to 0.3 mol/l).After about 15 min, ice-cooling is removed and the mixture is stirred atroom temperature for approximately 2-3 h, and the solution is thenconcentrated and dried under high vacuum. The residue is taken up indichloromethane or dichloromethane/methanol and washed with saturatedsodium bicarbonate or 1N sodium hydroxide solution. The organic phase iswashed with saturated sodium chloride solution, dried over a littlemagnesium sulphate and concentrated. If appropriate, purification iscarried out by crystallization from ether or ether/dichloromethanemixtures.

[0892] The following compounds were prepared in an analogous manner fromthe corresponding Boc-protected precursors:

Example 148N-({3-[4-(Aminomethyl)phenyl]-2-oxo1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide

[0893] starting from Example 92:

[0894] MS (ESI): m/z (%)=349 (M−NH₂, 25),305 (100);

[0895] HPLC (method 1): rt (%)=3.68 (98).

[0896] IC₅₀: 2.2 μM

Example 149N-{[3-(4-Aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide

[0897] starting from Example 93:

[0898] MS (ESI): m/z (%)=352 (M+H, 25);

[0899] HPLC (method 1): rt (%)=3.50 (100).

[0900] IC₅₀: 2 μM

[0901] An alternative enantiomerically pure synthesis of this compoundis shown in the scheme below (cf. also Delalande S. A., DE 2836305,1979;Chem. Abstr. 90, 186926):

Example 1505-Chloro-N-({3-[4-(glycylamino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0902] starting from Example 152:

[0903] MS (ES-pos): m/z (%)=408 (100);

[0904] HPLC (method 3): rt (%)=3.56 (97).

[0905] IC₅₀: 2 μM

Example 1515-(Aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl-1,3-oxazolidin-2-one

[0906] starting from Example 60:

[0907] MS (ESI): m/z (%)=276 (M+H, 100);

[0908] HPLC (method 3): rt (%)=2.99 (100).

[0909] IC₅₀: 2 μM

[0910] The Examples 152 to 166 below refer to the amino groupderivatization of aniline- or benzylamine-substituted oxazolidinonesusing various reagents:

Example 1525-Chloro-N-({3-[4-(N-tert-butyloxycarbonyl-glycylamino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0911]

[0912] At 0° C., 754 mg (2.1 mmol) ofN-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5chloro-2-thiophenecarboxamide(from Example 149) are added to a solution of 751 mg (4.3 mmol) ofBoc-glycine, 870 mg (6.4 mmol) of HOBT (1-hydroxy-1H-benzotriazole×H₂O),1790 mg (4.7 mmol) of HBTU[O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate]and 1.41 ml (12.9 mmol) of N-methylmorpholine in 15 ml of DM/CH₂Cl₂(1:1). The mixture is stirred at room temperature overnight and thendiluted with water. The precipitated solid is filtered off and dried.Yield: 894 mg (79.7% of theory);

[0913] MS (DCI, NH₃): m/z (%)=526 (M+NH₄, 100);

[0914] HPLC (method 3): rt (%)=4.17 (97).

Example 153N-[(3-{4-[(Acetylamino)methyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide

[0915]

[0916] At 0° C., a mixture of 30 mg (0.082 mmol) ofN-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide(from Example 148) in 1.5 ml of absolute THF and 1.0 ml of absolutedichloromethane, and 0.02 ml of absolute pyridine is mixed with aceticanhydride (0.015 ml, 0.164 mmol). The mixture is stirred at roomtemperature overnight. Addition of ether and crystallization affords theproduct. Yield: 30 mg (87% of theory),

[0917] MS (ESI): m/z (%)=408 (M+H, 18), 305 (85);

[0918] HPLC (method 1): rt (%)=3.78 (97).

[0919] IC₅₀: 0.6 μM

Example 154N-{[3-(4-{[(Aminocarbonyl)amino]methyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiophenecarboxamide

[0920]

[0921] At room temperature, 0.19 ml (0.82 mmol) oftrimethylsilylisocyanate are added dropwise to a mixture of 30 mg (0.082mmol) of N-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide (from Example 148) in 1.0 mlof dichloromethane. The mixture is stirred overnight and, after additionof ether, the product is then obtained by filtration. Yield: 21.1 mg(52% of theory),

[0922] MS (ESI): m/z (%)=409 (M+H, 5), 305 (72);

[0923] HPLC (method 1): rt (%)=3.67 (83).

[0924] IC₅₀: 1.3 μM

General Method for AcylatingN-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamidewith carbonyl chlorides

[0925]

[0926] Under argon, an approximately 0.1 molar solution ofN-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide(from Example 149) (1.0 eq.) in absolute dichloromethane/pyridine (19:1)is added dropwise to the appropriate acid chloride (2.5 eq.). Themixture is stirred overnight and then admixed with about 5 eq. of PStrisamine (Argonaut Technologies) and 2 ml of absolute dichloromethane.The mixture is stirred gently for 1 h and then filtered off, and thefiltrate is concentrated. If appropriate, the products are purified bypreparative RP-HPLC.

[0927] The following compounds were prepared in an analogous manner:

Example 155N-({3-[4-(Acetylamino)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide

[0928] LC-MS: m/z (%)=394 (M+H, 100);

[0929] LC-MS (method 6): rt (%)=3.25 (100)

[0930] IC₅₀: 1.2 μM

Example 1565-Chloro-N-[(2-oxo-3-{4-[(2-thienylcarbonyl)amino]phenyl}-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0931] LC-MS: m/z (%)=462 (M+H, 100);

[0932] LC-MS (method 6): rt (%)=3.87 (100).

[0933] IC₅₀: 1.3 μM

Example 1575-Chloro-N-[(3-{4-[(methoxyacetyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)-methyl]-2-thiophenecarboxamide

[0934] LC-MS: m/z (%)=424 (M+H, 100);

[0935] LC-MS (method 6): rt (%)=3.39 (100).

[0936] IC₅₀: 0.73 μM

Example 158N-{4-[5-({[(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-3,5-dimethyl-4-isoxazolecarboxamide

[0937] LC-MS: m/z (%)=475 (M+H, 100).

[0938] IC₅₀: 0.46 μM

Example 1595-Chloro-N-{[3-(4-{[(3-chloropropyl)sulphonyl]amino}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide

[0939]

[0940] An ice-cooled solution of 26.4 mg (0.15 mmol) of3-chloro-1-propanesulphonyl chloride and 0.03 ml (0.2 mmol) oftriethylamine in 3.5 ml of absolute dichloro methane is admixed with 35mg (0.1 mmol) of N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiophene-carboxamide (from Example 149). After 30 min,ice-cooling is removed and the mixture is stirred at room temperatureovernight, and 150 mg (about 5.5 eq.) of PS-trisamine (ArgonautTechnologies) and 0.5 ml of dichloromethane are then added. Thesuspension is stirred gently for 2 h and filtered (the resin is washedwith dichloromethane/methanol), and the filtrate is concentrated. Theproduct is purified by preparative RP-HPLC. Yield: 19.6 mg (40% oftheory),

[0941] LC-MS: m/z (%)=492 (M+H, 100);

[0942] LC-MS (method 5): rt (%)=3.82 (91).

[0943] IC₅₀: 1.7 μM

Example 1605-Chloro-N-({3-[4-(1,1-dioxido-2-isothiazolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

[0944]

[0945] A mixture of 13.5 mg (0.027 mmol) of5-chloro-N-{[3-(4-{[(3-chloropropyl)sulphonyl]amino}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophene-carboxamide (fromExample 159) and 7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml ofDMF is heated at 100° C. for 2 h. After cooling, the mixture is dilutedwith dichloromethane and washed with water. The organic phase is driedand concentrated. The residue is purified by preparative thin-layerchromatography (silica gel, dichloromethane/methanol, 95:5). Yield: 1.8mg (14.4% of theory), MS (ESI): m/z (%)=456 (M+H, 15), 412 (100);

[0946] LC-MS (method 4): rt (%)=3.81 (90).

[0947] IC₅₀: 0.14 μM

Example 1615-Chloro-N-[((5S)-3-{4(5-chloropentanoyl)amino]phenyl]-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0948]

[0949] 0.5 g (1.29 mmol) ofN-{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide(from Example 149) is dissolved in 27 ml of tetrahydrofuran and admixedwith 0.2 g (1.29 mmol) of 5-chlorovaleryl chloride and 0.395 ml (2.83mmol) of triethylamine. The mixture is concentrated under reducedpressure and chromatographed over silica gel using a toluene/ethylacetate=1:1 ->ethyl acetate gradient. This gives 315 mg (52% of theory)of a solid.

[0950] M.p.: 211° C.

Example 1625-Chloro-N-({(SS)-2-oxo-3-[4-(2-oxo-1-piperidinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

[0951]

[0952] Under inert conditions, 5 ml of DMSO are admixed with 30 mg ofNaH (60% in paraffin oil), and the mixture is heated at 75° C. for 30min, until the evolution of gas has ceased. A solution of 290 mg (0.617mmol) of5-chloro-N-[((5S)-3-{4-[(5-chloropentanoyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophene-carboxamide(from Example 161) in 5 ml of methylene chloride is then added dropwise,and the mixture is stirred at room temperature overnight. The reactionis terminated and the mixture is poured into 100 ml of water andextracted with ethyl acetate. The evaporated organic phase ischromatographed on an RP-8 column and the product is eluted withacetonitrile/water. This gives 20 mg (7.5% of theory) of the targetcompound.

[0953] M.p.: 205° C.;

[0954] NMR (300 MHz, d₆-DMSO): δ=1.85 (m,4H), 2.35 (m,2H), 3.58 (m,4H),3.85 (m,1H), 4.2 (t,1H), 4.82 (m,1H), 7.18 (d,1H,thiophene), 7.26(d,2H), 7.5 (d,2H), 2.68 (d,1H,thiophene), 9.0 (t,1H,CONH).

[0955] IC₅₀: 2.8 nM

Example 1635-Chloro-N-[((5S)-3-{4-[(3-bromopropionyl)arnino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0956]

[0957] is obtained in an analogous manner from Example 149.

Example 1645-Chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-1-azetidinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

[0958]

[0959] is obtained in an analogous manner by cyclization of theopen-chain bromopropionyl compound from Example 163 using NaH/DMSO.

[0960] MS (ESI): m/z (%)=406 ([M+H]⁺, 100), Cl pattern.

[0961] IC₅₀: 380 nM

Example 165 tert-Butyl4-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3oxazolidin-3-yl]phenyl}-3,5-dioxo-1-piperazinecarboxylate

[0962]

[0963] A solution of 199 mg (0.85 mmol) of Boc-iminodi acetic acid, 300mg (2.2 mmol) of HOBT, 0.66 ml (6 mmol) of N-methylmorpholine and 647 mg(1.7 mmol) of HBTU is admixed with 300 mg (0.85 mmol) ofN-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiophene-carboxamide in 6 ml of a mixture of DMF anddichloromethane (1:1). The mixture is stirred overnight, diluted withdichioromethane and then washed with water, saturated ammonium chloridesolution, saturated sodium bicarbonate solution, water and saturatedsodium chloride solution. The organic phase is dried over magnesiumsulphate and concentrated. The crude product is purified by silica gelchromatography (dichloromethanelmethanol 98:2). Yield: 134 mg (29% oftheory);

[0964] MS (ESI): m/z (%)=571 (M+Na, 82), 493 (100);

[0965] HPLC (method 3): rt (%)=4.39 (90).

[0966] IC₅₀: 2 μM

Example 166 N-[((5S)-3-{4-[(3R)-3-Amino-2-oxo-1 pyrrolidinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamidetrifluoroacetate

[0967]

N2-(tert-Butoxycarbonyl)-N1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-D-methionineamide

[0968] 429 mg (1.72 mmol) of N-BOC-D-methionine, 605 mg (1.72 mmol) ofN-{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide, and 527 mg (3.44 mmol) of HOBThydrate are dissolved in 35 ml of DMF and admixed with 660 mg (3.441mmol) of EDCI hydrochloride and then dropwise with 689 mg (5.334 mmol)of N-ethyl-diisopropylamine. The mixture is stirred at room temperaturefor two days. The resulting suspension is filtered off with suction andthe residue is washed with DMF. The combined filtrates are admixed witha little silica gel, concentrated under reduced pressure andchromatographed over silica gel using a toluene ->T10EA7 gradient. Thisgives 170 mg (17% of theory) of the target compound of melting point183° C.

[0969] R_(f) (SiO₂, toluene/ethyl acetate=1:1):0.2.

[0970]¹H-NMR (300 MHz, d₆-DMSO): δ=1.4 (s,1H,BOC), 1.88-1.95 (m,2H),2.08 (s,3H,SMe), 2.4-2.5 (m,2H, partially obscurbed by DMSO), 3.6(m,2H), 3.8 (m,1H), 4.15 (m,2H), 4.8 (m,1H), 7.2 (1H, thiophene), 7.42(d, part of an AB system, 2H), 7.6 (d, part of an AB system, 2H), 7.7(d, 1H, thiophene), 8.95 (t,1H, CH₂NHCO), 9.93 (bs, 1H,NH).

tert-Butyl(3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinylcarbamate

[0971] 170 mg (0.292 mmol) ofN2-(tert-butoxycarbonyl)-N1-(4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-D-methionine-amideare dissolved in 2 ml of DMSO and admixed with 178.5 mg (0.875 mmol) oftrimethylsulphonium iodide and 60.4 mg (0.437 mmol) of potassiumcarbonate, and the mixture is stirred at 80° C. for 3.5 hours. Themixture is then concentrated under high vacuum and the residue is washedwith ethanol. 99 mg of the target compound remain.

[0972]¹H-NMR (300 MHz, d₆-DMSO): δ=1.4 (s,1H,BOC), 1.88-2.05 (m,1; H),2.3-2.4 (m,1H), 3.7-3.8 (m,3H), 3.8-3.9 (m,IH), 4.14.25 (m,1H),4.25-4.45 (m,1H), 4.75-4.95 (m,1H), 7.15 (1H, thiophene), 7.25 (d,1H),7.52 (d, part of an AB system, 2H), 7.65 (d, part of an AB system, 2H),7.65 (d, 1H, thiophene), 9.0 (broad s,1H).

N[((5S)-3-{4-[(3R)-3-Amino-2-oxo-1-pyrrolidinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamidetrifluoroacetate

[0973] 97 mg (0.181 mmol) of tert-butyl(3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinylcarbamate are suspended in 4 ml of methylenechloride, 1.5 ml of trifluoroacetic acid are added and the mixture isstirred at room temperature for 1 hour. The mixture is then concentratedunder reduced pressure and the residue is purified on an RP-HPLC(acetonitrile/water/0.1% TFA gradient). Evaporation of the appropriatefraction gives 29 mg (37% of theory) of the target compound of meltingpoint 241° C. (decomp.).

[0974] R_(f) (SiO₂,EtOH/TEA=17:1) 0.19.

[0975]¹H-NMR (300 MHz, d₆-DMSO): δ=1.92-2.2 (m,1H), 2.4-2.55 (m,1H,partially obscured by DMSO peak), 3.55-3.65 (m,2H), 3.75-3.95 (m,3H),4.1-4.3 (m,2H), 4.75-4.9 (m,1H), 7.2 (1H, thiophene), 7.58 (d, part ofan AB system, 2H), 7.7 (d, part of an AB system, 2H), 7.68 (d, 1H,thiophene), 8.4 (broad s,3H, NH3), 8.9 (t,1H,NHCO).

[0976] The Examples 167 to 170 below refer to the introduction ofsulphonamide groups in phenyl-substituted oxazolidinones:

General Method for Preparing Substituted Sulphonamides Starting From5-chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0977]

[0978] Under argon and at 5° C.,5-chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide(from Example 96) is added to chlorosulphonic acid (12 eq.). Thereaction mixture is stirred at room temperature for 2 h and then pouredinto ice-water. The resulting precipitate is filtered off, washed withwater and dried.

[0979] Under argon and at room temperature, the precipitate is thendissolved in tetrahydrofuran (0.1 mol/l) and admixed with theappropriate amine (3 eq.), triethylamine (1.1 eq.) anddimethylaminopyridine (0.1 eq.). The reaction mixture is stirred for 1-2h and then concentrated under reduced pressure. The desired product ispurified by flash chromatography (dichloromethane/methanol mixtures).

[0980] The following compounds were prepared in an analogous manner:

Example 1675-Chloro-N-({2-oxo-3-[4-(1-pyrrolidinylsulphonyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

[0981] MS (ESI): m/z (%)=492 ([M+Na]⁺, 100), 470 ([M+H]⁺, 68), Clpattern;

[0982] HPLC (method 3): rt (%)=4.34 (100).

[0983] IC₅₀: 0.5 μM

Example 1685-Chloro-N-[(3-{4-[(4-methyl-1-piperazinyl)sulphonyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0984] MS (ESI): m/z (%)=499 ([M+H]⁺, 100), Cl pattem;

[0985] HPLC (method 2): rt (%)=3.3 (100).

Example 1695-Chloro-N-({2-oxo-3-[4-(1-piperidinylsulphonyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

[0986] MS (ESI): m/z (%)=484 ([M+H]⁺, 100), Cl pattern;

[0987] HPLC (method 2): rt (%)=4.4 (100).

Example 1705-Chloro-N-[(3-{4-[(4-hydroxy-1-piperidinyl)sulphonyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide

[0988] MS (ESI): m/z (%)=500 ([M+H]⁺, 100), Cl pattern;

[0989] HPLC (method 3): rt (%)=3.9 (100).

Example 1715-Chloro-N-({2-oxo-3-[4-(1-pyrrolidinyl)phenyl]-1,3-oxazolidin-5-yl}metbyl)-2-thiophenecarboxamide

[0990]

[0991] 780 mg (1.54 mmol) of tert-butyl1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}-methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}prolinateare dissolved in 6 ml of dichloromethane and 9 ml of trifluoroaceticacid, and the mixture is stirred at 40° C. for two days. The reactionmixture is then concentrated and stirred with ether and 2N aqueoussodium hydroxide solution. The aqueous phase is concentrated and stirredwith ether and 2N hydrochloric acid. The organic phase of thisextraction is dried over MgSO₄, filtered and concentrated. The crudeproduct is chromatographed over silica gel (CH₂Cl₂/EtOH/conc. aqu. NH₃sol.=100/1/0.1 to 20/1/0.1).

[0992] This gives 280 mg (40% of theory) of the product.

[0993] MS (ESI): m/z (%)=406 (M+H, 100);

[0994] HPLC (method 4): rt=3.81 min.

[0995] HPLC parameter and LC-MS parameter for the HPLC and LC-MS datagiven in the examples above (the unit of the retention time (rt) isminutes):

[0996] [1] Column: Kromasil C18, L-R temperature: 30° C., flow rate=0.75ml min⁻¹, eluent: A=0.01 M HClO₄, B=CH₃CN, gradient: ->0.5 min 98%A->4.5 min 10%A ->6.5 min 10% A

[0997] [2] Column: Kromasil C18 60*2, L-R temperature: 30° C., flowrate=0.75 ml min⁻¹, eluent: A=0.01 M H₃PO₄, B=CH₃CN, gradient: ->0.5 min90%A ->4.5 min 10%A ->6.5 min 10% A

[0998] [3] Column: Kromasil C18 60*2, L-R temperature: 30° C., flowrate=0.75 ml min⁻¹, eluent: A=0.005 M HClO₄, B=CH₃CN, gradient: ->0.5min 98%A ->4.5 min 10% A ->6.5 min 10% A

[0999] [4] Column: Symmetry C18 2.1×50 mm, column oven: 50° C., flowrate=0.6 ml min⁻¹, eluent: A=0.6 g 30% strength HCl/l of water, B=CH₃CN,gradient: 0.0 min 90% A ->4.0 min 10% A ->9 min 10% A

[1000] [5] MHZ-2Q, Instrument Micromass Quattro LCZ Column Symmetry C18,50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flow rate 0.5 ml min, eluentA=CH₃CN+0.1% formic acid, eluent B=water+0.1% formic acid, gradient: 0.0min 10% A ->4 min 90% A ->6 min 90% A

[1001] [6] MHZ-2P, Instrument Micromass Platform LCZ Column SymmetryC18, 50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flow rate=0.5 ml min⁻¹,eluent A=CH₃CN+0.1% formic acid, eluent B=water+0.1% formic acid,gradient: 0.0 min 10% A ->4 min 90% A ->6 min 90% A

[1002] [7] MHZ-7Q, Instrument Micromass Quattro LCZ Column Symmetry C18,50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flow rate=0.5 ml min⁻¹,eluent A=CH₃CN+0.1% formic acid, eluent B=water+0.1% formic acid,gradient: 0.0 min 5% A ->1 min 5% A ->5 min 90% A ->6 min 90% A

General Method for Preparing Oxazolidinones of the General Formula B bySolid-Phase-Supported Synthesis

[1003] Reactions with different resin-bonded products were carried outin a set of separated reaction vessels.

[1004] 5-(Bromomethyl)-3-(4-fluoro-3-nitrophenyl)-1,3-oxazolidin-2-one A(prepared from epibromohydrin and 4-fluoro-3-nitrophenyl isocyanateusing LiBr/Bu₃PO in xylene analogously to U.S. Pat. No. 4,128,654, Ex.2)(1.20 g, 3.75 mmol) and ethyldiisopropylamine (DREA, 1.91 ml, 4.13 mmol)were dissolved in DMSO (70 ml), admixed with a secondary amine (1.1 eq.,amine component 1) and reacted at 55° C. for 5 h. TentaGel SAM resin(5.00 g, 0.25 mmol/g) was added to this solution, and the mixture wasreacted at 75° C. for 48 h. The resin was filtered, washed repeatedlywith methanol (MeOH), dimethylformamide (DMF), MeOH, dichloromethane(DCM) and diethyl ether and dried. The resin (5.00 g) was suspended indichloromethane (80 ml), admixed with DEEA (10 eq.) and5-chlorothiophene-2-carbonyl chloride [prepared by reacting5-chlorothiophene-2-carboxylic acid (5 eq.) and1-chloro-1-dimethylamino-2-methylpropene (5 eq.) in DCM (20 ml) at roomtemperature for 15 minutes] and the mixture was reacted at roomtemperature for 5 h. The resulting resin was filtered, washed repeatedlywith MeOH, DCM and diethyl ether and dried. The resin was then suspendedin DMF/water (v/v 9:2, 80 ml), admixed with SnCl₂*2H₂O (5 eq.) andreacted at room temperture for 18 h. The resin was washed repeatedlywith MeOH, DMF, water, MeOH, DCM and diethyl ether and dried. This resinwas suspended in DCM, admixed with DIEA (10 eq.) and, at 0° C., with anacid chloride (5 eq. of acid derivative 1), and the mixture was reactedat room temperature overnight. Prior to the reaction, carboxylic acidswere converted into the corresponding acid chlorides by reaction with1-dimethylarnino-1-chloro-2-methylpropene (1 eq., based on thecarboxylic acid) in DCM at room temperature for 15 min. The resin waswashed repeatedly with DMF, water, DMF, MeOH, DCM and diethyl ether anddried. If the acid derivative 1 used was an Fmoc-protected amino acid,the Fmoc protective group was removed in the last reaction step byreaction with piperidine/DMF (v/v, ¼) at room temperature for 15minutes, and the resin was washed with DMF, MeOH, DCM and diethyl etherand dried. The products were then removed from the solid phase usingtrifluoroacetic acid (TFA)/DCM (v/v, 1/1), the resin was filtered offand the reaction solutions were concentrated. The crude products werefiltered over silica gel (DCM/MeOH, 9:1) and evaporated, giving a set ofproducts B.

[1005] Compounds which were prepared by solid-phase-supported synthesis:

Example 172N-({3-[3-Amino-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide

[1006]

[1007] Analogously to the general procedure for preparing thederivatives B, 5 g (1.25 mmol) of TentaGel SAM resin were reacted withpyrrolidine as amine derivative 1. The aniline obtained after reductionwith SnCl₂*2H₂O was, without any further acylation step, removed fromthe solid phase and concentrated. The crude product was partitionedbetween ethyl acetate and NaHCO₃ solution and the organic phase wassalted out using NaCl, decanted and evaporated to dryness. This crudeproduct was purified by vacuum flash chromatography over silica gel(dichloromethane/ethyl acetate, 3:1 - 1:2).

[1008]¹H-NMR (300 MHz, CDCl₃): 1.95-2.08, br, 4 H; 3.15-3.30, br, 4 H;3.65-3.81, m, 2 H; 3.89, ddd, 1H; 4.05, dd, 1 H; 4.81, dddd, I H; 6.46,dd, 1 H; 6.72, dd, 1 H; 6.90, dd, 1 H; 6.99, dd, 1 H; 7.03, dd, 1 H;7.29, d, 1 H.

Example 173N-[(3-{3-(B-Alanylamino)-4-[(3-hydroxypropyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide

[1009]

[1010] Analogously to the general procedure for preparing thederivatives B, 5 g (1.25 mmol) of TentaGel SAM resin were reacted withazetidine as amine derivative 1 and Fmoc-β-alanine as acid derivative 1.The crude product obtained after the removal was stirred in methanol atroom temperature for 48 h and evaporated to dryness. This crude productwas purified by reversed phase HPLC using a water/TFA/acetonitrilegradient.

[1011]¹H-NMR (400 MHz, CD₃OD): 2.31, tt, 2 H; 3.36, t, 2 H; 3.54, t, 2H; 3.62, t, 2 H; 3.72, dd, 1 H; 3.79, dd, 1 H; 4.01, dd, 1 H; 4.29, dd,2 H; 4.43, t, 2 H; 4.85-4.95, m, 1 H; 7.01, d, 1 H; 4.48-7.55, m, 2 H;7.61, d, 1 H; 7.84, d, 1 H.

Example 174N-({3-[4-(3-Amino-1-pyrrolidinyl)-3-nitrophenyl]-2-oxo-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophenecarboxamide

[1012]

[1013] Analogously to the general procedure for preparing thederivatives B, 130 mg (32.5 μmol) of TentaGel SAM resin were reactedwith tert-butyl 3-pyrrolidinylcarbamate as amine derivative 1. Thenitrobenzene derivative obtained after the acylation with5-chlorothiophenecarboxylic acid was removed from the solid phase andconcentrated. This crude product was purified by reversed phase HPLCusing a water/TFA/acetonitrile gradient.

[1014]¹H-NMR (400 MHz, CD₃OH): 2.07-2.17, m, 1 H; 2.39-2.49, m, 1 H;3.21-3.40, m, 2 H; 3.45, dd, 1 H; 3.50-3.60, m, 1 H; 3.67, dd, I H;3.76, dd, 1 H; 3.884.00, m, 2 H; 4.14-4.21, t, 1 H; 4.85-4.95, m, 1 H;7.01, d, 1 H; 7.11, d, 1 H; 7.52, d, 1 H; 7.66, dd, 1 H; 7.93, d, 1 H.

Example 175 N- ({3-[3-Amino-4-(1-piperidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl }methyl)-5-chloro-2-thiophenecarboxanide

[1015]

[1016] Analogously to the general procedure for preparing thederivatives B, 130 mg (32.5 μmol) of TentaGel SAM resin were reactedwith piperidine as amine derivative 1. The aniline obtained after thereduction was, without any further acylation step, removed from thesolid phase and concentrated. This crude product was purified byreversed phase HPLC using a water/TFA/acetonitrile gradient.

[1017]¹H-NMR (400 MHz, CD₃OH): 1.65-1.75, m, 2 H; 1.84-1.95, m, 4 H;3.20-3.28, m, 4 H; 3.68, dd, 1 H; 3.73, dd, 1H; 3.90, dd, 1 H; 4.17, dd,1 H; 4.804.90, m, 1 H; 7.00, d, 1 H; 7.05, dd, 1 H; 7.30-7.38, m, 2H;7.50, d, 1 H.

Example 176N-({3-[3-(Acetylamnino)-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}-methyl)-5-chloro-2-thiophenecarboxamide

[1018]

[1019] Analogously to the general procedure for preparing thederivatives B, 130 mg (32.5 μmol) of TentaGel SAM resin were reactedpyrrolidine as amine derivative 1 and acetyl chloride as acidderivative 1. The crude product was partitioned between ethyl acetateNaHCO₃ solution and the organic phase was salted out using NaCl,decanted and evaporated to dryness. This crude product was purified byvacuum flash chromatography over silica gel (dichloromethane/ethylacetate, 1:1-0:1).

[1020]¹H-NMR (400 MHz, CD₃OH): 1.93-2.03, br, 4 H; 2.16, s, 3 H;3.20-3.30, br, 4 H; 3.70, d, 2 H; 3.86, dd, 1H; 4.10, dd, 1 H; 4.14, dd,1 H; 4.80-4.90, m, 1 H; 7.00, d, 1 H; 7.07, d, 1 H; 7.31, dd, 1 H; 7.51,d, 1 H; 7.60, d, 1 H.

[1021] The following compounds were prepared analogously to the generalprocedure. Ret. HPLC Example Structure time [%] 177

2.62 79.7 178

2.49 33.7 179

4.63 46.7 180

3.37 44.8 181

2.16 83 182

2.31 93.3 183

2.7 100 184

3.91 51 185

2.72 75.2 186

3.17 46 187

4.61 50.2 188

3.89 56.6 189

3.37 52.9 190

3.6 63.9 191

2.52 70.1 192

3.52 46.6 193

2.87 50.1 194

3.25 71.1 195

2.66 67 196

2.4 52.1 197

3.13 48.9 198

2.67 75.5 199

2.72 65.7 200

2.71 57.3 201

2.22 100 202

3.89 75.7 203

3.19 49.6 204

2.55 88.2 205

2.44 68.6 206

2.86 71.8 207

2.8 63.6 208

2.41 77 209

2.56 67.9 210

3.67 78.4 211

2.54 69.8 212

3.84 59.2 213

2.41 67.8 214

2.41 75.4 215

4.01 81.3 216

3.46 49.5 217

4.4 60.2 218

3.79 70.9 219

4.57 51.5 220

2.68 100 221

4.53 63.5 222

2.66 89.2 223

4.76 69.3 224

3.45 77.4 225

3.97 63.2 226

3.94 61.4 227

4.15 66.3 228

4.41 55.1 229

2.83 41.1 230

2.7 83 231

4.39 64.2 232

4.85 74.9 233

4.17 41 234

4.21 61.8 235

2.75 100 236

3.94 50 237

4.65 75.8 238

4.4 75.3 239

4.24 62.2 240

4.76 75.1 241

4.17 72.5 242

4.6 74.8 243

4.12 51.6 244

4.71 66.2 245

4.86 62 246

5.23 58.3 247

4.17 72.4 248

3.35 59.6 249

2.41 60.3 250

3.31 65.2 251

2.86 36.5 252

2.69 89.8 253

2.81 67.4 254

2.19 75.4

[1022] All products of the solid-phase-supported synthesis werecharacterized by LC-MS. As standard, the following separation system wasused: HP 1100 with UV detector (208-400 nm), oven temperature 40° C.,Waters-Symmetry C18 column (50 mm×2.1 mm, 3.5 μm), mobile phase A: 99.9%acetonitrile/0.1% formic acid, mobile phase B: 99.9% water/0.1% formicacid; gradient: Time A: % B: % flow rate 0.00 10.0 90.0 0.50 4.00 90.010.0 0.50 6.00 90.0 10.0 0.50 6.10 10.0 90.0 1.00 7.50 10.0 90.0 0.50

[1023] The substances were detected using a Micromass Quattro LCZ MS,ionization: ESI positive/negative.

[1024] In the structures listed above which comprise the radical(s)

[1025] O, what is meant is in each case a

[1026] or —OH function.

1. Compounds of the general formula (I)

in which: R¹ represents optionally benzo-fused thiophene (thienyl) whichmay optionally be mono- or polysubstituted; R² represents any organicradical; R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and eachrepresents hydrogen or represents (C₁-C₆)-alkyl and theirpharmaceutically acceptable salts, hydrates and prodrugs, except forcompounds of the general formula (I) in which the radical R¹ is anunsubstituted 2-thiophene radical and the radical R² is simultaneously amono- or polysubstituted phenyl radical and the radicals R³, R⁴, R⁵, R⁶,R⁷ and R⁸ are each simultaneously hydrogen.
 2. Compounds of the generalformula (I) according to claim 1, characterized in that R¹ representsoptionally benzo-fused thiophene (thienyl) which may optionally be mono-or polysubstituted by a radical from the group consisting of halogen;cyano; nitro; amino; aminomethyl; (C₁-C₈)-alkyl which for its part mayoptionally be mono- or polysubstituted by halogen; (C₃-C₇)-cycloalkyl;(C₁-C₈)-alkoxy; imidazolinyl; —C(═NH)NH₂; carbamoyl; and mono- anddi-(C₁-C₄)-alkyl-aminocarbonyl, R² represents one of the groups below:A-, A-M-, D-M-A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B-, where: the radical“A” represents (C₆-C₁₄)-aryl, preferably (C₆-C₁₀)-aryl, in particularphenyl or naphthyl, very particularly preferably phenyl; the radical “B”represents a 5- or 6-membered aromatic heterocycle which contains up to3 heteroatoms and/or hetero chain members, in particular up to 2heteroatoms and/or hetero chain members, from the group consisting of S,N, NO (N-oxide) and O; the radical “D” represents a saturated orpartially unsaturated, mono- or bicyclic, optionally benzo-fused 4- to9-membered heterocycle which contains up to three heteroatoms and/orhetero chain members from the group consisting of S, SO, SO₂, N, NO(N-oxide) and O; the radical “M” represents —NH—, —CH₂—, —CH₂CH₂—, —O—,—NH—CH₂—, —CH₂—NH—, —OCH₂—, —CH₂O—, —CONH—, —NHCO—, —COO—, —OOC—, —S—,—SO₂— or represents a covalent bond; where the groups “A”, “B” and “D”defined above may each optionally be mono- or polysubstituted by aradical from the group consisting of halogen; trifluoromethyl; oxo;cyano; nitro; carbamoyl; pyridyl; (C₁-C₆)-alkanoyl;(C₃-C₇)-cycloalkanoyl; (C₆-C₁₄)-arylcarbonyl;(C₅-C₁₀)-heteroarylcarbonyl; (C₁-C₆)-alkanoyloxymethyloxy;(C₁-C₄)-hydroxy-alkylcarbonyl; —COOR²⁷; —SO₂R²⁷; —C(NR²⁷R²⁸)═NR²⁹;—CONR²⁸R²⁹; —SO₂NR²⁸R²⁹; —OR³⁰; —NR³⁰R³¹, (C₁-C₆)-alkyl and(C₃-C₇)-cycloalkyl, where (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl for theirpart may optionally be substituted by a radical from the groupconsisting of cyano; —OR²⁷; —NR²⁸R²⁹; —O(NH)_(v)(NR²⁷R²⁸) and —C(NR²⁷R²⁸)═NR²⁹, where: v is either 0 or 1 and R²⁷, R²⁸ and R²⁹ are identicalor different and independently of one another each represents hydrogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, (C₁-C₄)-alkanoyl, carbamoyl,trifluoromethyl, phenyl or pyridyl, and/or R²⁷ and R²⁸ or R²⁷ and R²⁹together with the nitrogen atom to which they are attached form asaturated or partially unsaturated 5- to 7-membered heterocycle havingup to three, preferably up to two, identical or different heteroatomsfrom the group consisting of N, O and S, and R³⁰ and R³¹ are identicalor different and independently of one another each represents hydrogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, (C₁-C₄)-alkylsulphonyl,(C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl,di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, —CH₂C(NR²⁷R²⁸)═NR²⁹ or —COR³³,where R³³ represents (C₁-C₆)-alkoxy, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,(C₁-C₄)-alkoxycarbonyl-(C₁-C₄)-alkyl, (C₁-C₄)-aminoalkyl,(C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkanoyl-(C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, (C₁-C₆)-alkenyl, (C₁-C₈)-alkyl, which may optionallybe substituted by phenyl or acetyl, (C₆-C₁₄)-aryl, (C₅-C₁₀)-heteroaryl,trifluoromethyl, tetrahydrofuranyl or butyrolactone, R³, R⁴, R⁵, R⁶, R⁷and R⁸ are identical or different and each represents hydrogen orrepresents (C₁-C₆)-alkyl and their pharmaceutically acceptable salts,hydrates and prodrugs, except for compounds of the general formula (I)in which the radical R¹ is an unsubstituted 2-thiophene radical and theradical R² is simultaneously a mono- or polysubstituted phenyl radicaland the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneouslyhydrogen.
 3. Compounds of the general formula (I) according to claim 1,characterized in that R¹ represents thiophene (thienyl), in particular2-thiophene, which may optionally be mono- or polysubstituted byhalogen, preferably chlorine or bromine, by amino, aminomethyl or(C₁-C₈)-alkyl, preferably methyl, where the (C₁-C₈)-alkyl radical forits part may optionally be mono- or polysubstituted by halogen,preferably fluorine, R² represents one of the groups below: A-, A-M-,D-M-A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B-, where: the radical “A”represents (C₆-C₁₄)-aryl, preferably (C₆-C₁₀)-aryl, in particular phenylor naphthyl, very particularly preferably phenyl; the radical “B”represents a 5- or 6-membered aromatic heterocycle which contains up to3 heteroatoms and/or hetero chain members, in particular up to 2heteroatoms and/or hetero chain members, from the group consisting of S,N, NO (N-oxide) and O; the radical “D” represents a saturated orpartially unsaturated 4- to 7-membered heterocycle which contains up tothree heteroatoms and/or hetero chain members from the group consistingof S, SO, SO₂, N, NO (N-oxide) and O; the radical “M” represents —NH—,—CH₂—, —CH₂CH₂—, —O—, —NH—CH₂—, —CH₂—NH—, —OCH₂—, —CH₂O—, —CONH—,—NHCO—, —COO—, —OOC—, —S— or represents a covalent bond; where thegroups “A”, “B” and “D” defined above may in each case optionally bemono- or polysubstituted by a radical from the group consisting ofhalogen; trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl;(C₁-C₆)-alkanoyl; (C₃-C₇)-cycloalkanoyl; (C₆-C₁₄)-arylcarbonyl;(C₅-C₁₀)-heteroaryl-carbonyl; (C₁-C₆)-alkanoyloxymethyloxy; —COOR²⁷;—SO₂R²⁷; —C(NR²⁷R²⁸)═NR²⁹; —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹; —OR³⁰; —NR³⁰R³¹,(C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, where (C₁-C₆)-alkyl and(C₃-C₇)-cycloalkyl for their part may optionally be substituted by aradical from the group consisting of cyano; —OR²⁷; —NR²⁸R²⁹;—CO(NH)_(v)(NR²⁷R²⁸) and —C(NR²⁷R²⁸)═NR²⁹, where: v is either 0 or 1 andR²⁷, R²⁸ and R²⁹ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl,and/or R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom towhich they are attached form a saturated or partially unsaturated 5- to7-membered heterocycle having up to three, preferably up to two,identical or different heteroatoms from the group consisting of N, O andS, and R³⁰ and R³¹ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₁-C₄)-alkylsulphonyl, (C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl,di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, (C₁-C₄)-alkanoyl,(C₆-C₁₄)-arylcarbonyl, (C₅-C₁₀)-heteroarylcarbonyl,(C₁-C₄)-alkylaminocarbonyl or —CH₂C(NR²⁷R²⁸)═NR²⁹, R³, R⁴, R⁵, R⁶, R⁷and R⁸ are identical or different and each represents hydrogen orrepresents (C₁-C₆)-alkyl and their pharmaceutically acceptable salts,hydrates and prodrugs, except for compounds of the general formula (I)in which the radical R¹ is an unsubstituted 2-thiophene radical and theradical R² is simultaneously a mono- or polysubstituted phenyl radicaland the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneouslyhydrogen.
 4. Compounds of the general formula (I) according to claim 1,characterized in that R¹ represents thiophene (thienyl), in particular2-thiophene, which may optionally be mono- or polysubstituted byhalogen, preferably chlorine or bromine, or by (C₁-C₈)-alkyl, preferablymethyl, where the (C₁-C₈)-alkyl radical for its part may optionally bemono- or polysubstituted by halogen, preferably fluorine, R² representsone of the groups below: A-, A-M-, D-M-A-, B-M-A-, B-, B-M-, B-M-B-,D-M-B-, where: the radical “A” represents phenyl or naphthyl, inparticular phenyl; the radical “B” represents a 5- or 6-memberedaromatic heterocycle which contains up to 2 heteroatoms from the groupconsisting of S, N, NO (N-oxide) and O; the radical “D” represents asaturated or partially unsaturated 5- or 6-membered heterocycle whichcontains up to two heteroatoms and/or hetero chain members from thegroup consisting of S, SO, SO₂, N, NO (N-oxide) and O; the radical “M”represents —NH—, —O—, —NH—CH₂—, —CH₂—NH—, —OCH₂—, —CH₂O—, —CONH—, —NHCO—or represents a covalent bond; where the groups “A”, “B” and “D” definedabove may in each case optionally be mono- or polysubstituted by aradical from the group consisting of halogen; trifluoromethyl; oxo;cyano; pyridyl; (C₁-C₃)-alkanoyl; (C₆-C₁₀)-arylcarbonyl;(C₅-C₆)-heteroarylcarbonyl; (C₁-C₃)-alkanoyloxymethyloxy;—C(NR²⁷R²⁸)═NR²⁹; —CONR²⁸R²⁹; —SO₂NR²⁸R²⁹; —OH; —NR³⁰R³¹; (C₁-C₄)-alkyl;and cyclopropyl, cyclopentyl or cyclohexyl, where (C₁-C₄)-alkyl andcyclopropyl, cyclopentyl or cyclohexyl for their part may optionally besubstituted by a radical from the group consisting of cyano; —OH; —OCH₃;—NR²⁸R²⁹; —CO(NH)_(v)(NR²⁸R²⁹) and —C(NR²⁷R²⁸)═NR²⁹, where: v is either0 or 1, preferably 0, and R²⁷, R²⁸ and R²⁹ are identical or differentand independently of one another each represents hydrogen, (C₁-C₄)-alkylor else cyclopropyl, cyclopentyl or cyclohexyl and/or R²⁷ and R²⁸ or R²⁷and R²⁹ together with the nitrogen atom to which they are attached mayform a saturated or partially unsaturated 5- to 7-membered heterocyclehaving up to two identical or different heteroatoms from the groupconsisting of N, O and S, and R³⁰ and R³¹ are identical or different andindependently of one another each represents hydrogen, (C₁-C₄)-alkyl,cyclopropyl, cyclopentyl, cyclohexyl, (C₁-C₄)-alkylsulphonyl,(C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl,di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, (C₁-C₃)-alkanoyl or phenylcarbonyl,R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each representshydrogen or represents (C₁-C₆)-alkyl and their pharmaceuticallyacceptable salts, hydrates and prodrugs, except for compounds of thegeneral formula (I) in which the radical R¹ is an unsubstituted2-thiophene radical and the radical R² is simultaneously a mono- orpolysubstituted phenyl radical and the radicals R³, R⁴, R⁵, R⁶, R⁷ andR⁸ are each simultaneously hydrogen.
 5. Compounds of the general formula(I) according to claim 1, characterized in that R¹ represents2-thiophene which may optionally be substituted in the 5-position by aradical from the group consisting of chlorine, bromine, methyl ortrifluoromethyl, R² represents one of the groups below: A-, A-M-,D-M-A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B, where: the radical “A”represents phenyl or naphthyl, in particular phenyl; the radical “B”represents a 5- or 6-membered aromatic heterocycle which contains up to2 heteroatoms from the group consisting of S, N, NO (N-oxide) and O; theradical “D” represents a saturated or partially unsaturated 5- or6-membered heterocycle which contains a nitrogen atom and optionally afurther heteroatom and/or hetero chain member from the group consistingof S, SO, SO₂ and O; or contains up to two heteroatoms and/or heterochain members from the group consisting of S, SO, SO₂ and O; the radical“M” represents —NH—, —O—, —NH—CH₂—, —CH₂—NH—, —OCH₂—, —CH₂O—, —CONH—,—NHCO— or represents a covalent bond; where the groups “A”, “B” and “D”defined above may in each case optionally be mono- or polysubstituted bya radical from the group consisting of halogen; trifluoromethyl; oxo;cyano; pyridyl; (C₁-C₃)-alkanoyl; (C₆-C₁₀)-arylcarbonyl;(C₅-C₆)-heteroarylcarbonyl; (C₁-C₃)-alkanoyloxymethyloxy; —CONR²⁷R²⁹;—SO₂NR²⁸R²⁹; —OH; —NR³⁰R³¹; (C₁-C₄)-alkyl; and cyclopropyl, cyclopentylor cyclohexyl, where (C₁-C₄)-alkyl and cyclopropyl, cyclopentyl orcyclohexyl for their part may optionally be substituted by a radicalfrom the group consisting of cyano; —OH; —OCH₃; —NR²⁸R²⁹;—CO(NH)_(v)(NR²⁷R²⁸) and —C(NR²⁷R²⁸)═NR²⁹, where: v is either 0 or 1,preferably 0, and R²⁷, R²⁸ and R²⁹ are identical or different andindependently of one another each represents hydrogen, (C₁-C₄)-alkyl orelse cyclopropyl, cyclopentyl or cyclohexyl and/or R²⁷ and R²⁸ or R²⁷and R²⁹ together with the nitrogen atom to which they are attached mayform a saturated or partially unsaturated 5- to 7-membered heterocyclehaving up to two identical or different heteroatoms from the groupconsisting of N, O and S, and R³⁰ and R³¹ are identical or different andindependently of one another each represents hydrogen, (C₁-C₄)-alkyl,cyclopropyl, cyclopentyl, cyclohexyl, (C₁-C₄)-alkylsulphonyl,(C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl, di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, (C₁-C₃)-alkanoyl or phenylcarbonyl, R³, R⁴, R⁵, R⁶,R⁷ and R⁸ are identical or different and each represents hydrogen orrepresents (C₁-C₄)-alkyl and their pharmaceutically acceptable salts,hydrates and prodrugs, except for compounds of the general formula (I)in which the radical R¹ is an unsubstituted 2-thiophene radical and theradical R² is simultaneously a mono- or polysubstituted phenyl radicaland the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneouslyhydrogen.
 6. Compounds of the general formula (I) according to claim 1,characterized in that R¹ represents 2-thiophene which is substituted inthe 5-position by a radical from the group consisting of chlorine,bromine, methyl and trifluoromethyl, R² represents D-A-: where: theradical “A” represents phenylene; the radical “D” represents a saturated5- or 6-membered heterocycle, which is attached to “A” via a nitrogenatom, which has a carbonyl group directly adjacent to the linkingnitrogen atom and in which one carbon ring member may be replaced by aheteroatom from the group consisting of S, N and O; where the group “A”defined above may optionally be mono- or disubstituted in the metaposition with respect to the point of attachment to the oxazolidinone,by a radical from the group consisting of fluorine, chlorine, nitro,amino, trifluoromethyl, methyl and cyano, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ eachrepresent hydrogen and their pharmaceutically acceptable salts, hydratesand prodrugs.
 7. Compound according to claim 1 having the followingformula

and its pharmaceutically acceptable salts, hydrates and prodrugs. 8.Process for preparing substituted oxazolidinones according to claims 1to 7, where either according to a process alternative [A] compounds ofthe general formula (II)

in which the radicals R², R³, R⁴, R⁵, R⁶ and R⁷ are each as defined inclaim 1 are reacted with carboxylic acids of the general formula (III)

in which the radical R¹ is as defined in claim 1, or else with thecorresponding carbonyl halides, preferably carbonyl chlorides, or elsewith the corresponding symmetric or mixed carboxylic anhydrides of thecarboxylic acids of the general formula (II) defined above in inertsolvents, if appropriate in the presence of an activating or couplingagent and/or a base, to give compounds of the general formula (I)

in which the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each asdefined in claim 1, or else according to a process alternative [B]compounds of the general formula (IV)

in which the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as definedin claim 1, are converted, using a suitable selective oxidizing agent inan inert solvent, into the corresponding epoxide of the general formula(V)

in which the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as definedin claim 1, and, by reaction in an inert solvent, if appropriate in thepresence of a catalyst, with an amine of the general formula (VI)R²—NH₂  (VI), in which the radical R² is as defined in claim 1, thecompounds of the general formula (VII)

in which the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each asdefined in claim 1, are initially prepared and, subsequently, in aninert solvent in the presence of phosgene or phosgene equivalents, suchas, for example, carbonyldiimidazole (CDI), cyclized to give thecompounds of the general formula (I)

in which the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each asdefined in claim 1, where—both for process alternative [A] and forprocess alternative [B]—in the case where R² contains a 3- to 7-memberedsaturated or partially unsaturated cyclic hydrocarbon radical having oneor more identical or different heteroatoms from the group consisting ofN and S, an oxidation with a selective oxidizing agent to afford thecorresponding sulphone, sulphoxide or N-oxide may follow and/orwhere—both for process alternative [A] and for process alternative[B]—in the case where the compound prepared in this manner has a cyanogroup in the molecule, an amidination of this cyano group by customarymethods may follow and/or where—both for process alternative [A] and forprocess alternative [B]—in the case where the compound prepared in thismanner has a BOC amino protective group in the molecule, removal of thisBOC amino protective group by customary methods may follow and/orwhere—both for process alternative [A] and for process alternative[B]—in the case where the compound prepared in this manner has ananiline or benzylamine radical in the molecule, a reaction of this aminogroup with various reagents such as carboxylic acids, carboxylicanhydrides, carbonyl chlorides, isocyanates, sulphonyl chlorides oralkyl halides to give the corresponding derivatives may follow and/orwhere—both for process alternative [A] and for process alternative[B]—in the case where the compound prepared in this manner has a phenylring in the molecule, a reaction with chlorosulphonic acid andsubsequent reaction with amines to give the corresponding sulphonarnidesmay follow.
 9. Medicaments, comprising at least one compound of thegeneral formula (I) according to claims 1 to 7 and one or morepharmacologically acceptable auxiliaries or excipients.
 10. Use ofcompounds of the general formula (I)

in which: R¹ represents optionally benzo-fused thiophene (thienyl) whichmay optionally be mono- or polysubstituted; R² represents any organicradical; R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and eachrepresents hydrogen or represents (C₁-C₆)-alkyl and theirpharmaceutically acceptable salts, hydrates and prodrugs, for preparingmedicaments or pharmaceutical compositions for the prophylaxis and/ortreatment of thromboembolic disorders, in particular myocardial infarct,angina pectoris (including unstable angina), reocclusions and restenosesafter angioplasty or aorto-coronary bypass, stroke, transitory ischaemicattacks, peripheral arterial occlusive diseases, pulmonary embolisms ordeep venous thromboses.
 11. Use of compounds of the general formula (I)according to claim 10 for preparing medicaments or pharmaceuticalcompositions for the prophylaxis and/or treatment of disorders which areinfluenced positively by inhibition of factor Xa.
 12. Use of compoundsof the general formula (I) according to claim 10 for preparingmedicaments or pharmaceutical compositions for the treatment ofdisseminated intravascular coagulation (DIC).
 13. Use of compounds ofthe general formula (I) according to claim 10 for preparing medicamentsor pharmaceutical compositions for the prophylaxis and/or treatment ofdisorders such as atherosclerosis; arthritis; Alzheimer's disease orcancer.
 14. Use of compounds of the general formula (I) according toclaim 10 for preparing medicaments or pharmaceutical compositions forthe inhibition of factor Xa.
 15. Method for preventing the coagulationof blood in vitro, in particular in the case of banked blood orbiological samples containing factor Xa, characterized in that compoundsof the general formula (I) according to claim 10 are added.